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Biosci. Rep. (2009) / 29 / 193–209 (Printed in Great Britain) /
doi 10.1042/BSR20090032
Rab7: roles in membrane trafficking and diseaseMing ZHANG, Li
CHEN, Shicong WANG and Tuanlao WANG1
Institute for Biomedical Research, Xiamen University, Xiamen,
Fujian, 361005, People’s Republic of China
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SynopsisThe endocytosis pathway controls multiple cellular and
physiological events. The lysosome is the destination ofnewly
synthesized lysosomal hydrolytic enzymes. Internalized molecules or
particles are delivered to the lysosomefor degradation through
sequential transport along the endocytic pathway. The endocytic
pathway is also emergingas a signalling platform, in addition to
the well-known role of the plasma membrane for signalling. Rab7 is
a lateendosome-/lysosome-associated small GTPase, perhaps the only
lysosomal Rab protein identified to date. Rab7plays critical roles
in the endocytic processes. Through interaction with its partners
(including upstream regulatorsand downstream effectors), Rab7
participates in multiple regulation mechanisms in endosomal
sorting, biogenesis oflysosome [or LRO (lysosome-related
organelle)] and phagocytosis. These processes are closely related
to substratesdegradation, antigen presentation, cell signalling,
cell survival and microbial pathogen infection. Consistently,
muta-tions or dysfunctions of Rab7 result in traffic disorders,
which cause various diseases, such as neuropathy, cancerand lipid
metabolism disease. Rab7 also plays important roles in microbial
pathogen infection and survival, as wellas in participating in the
life cycle of viruses. Here, we give a brief review on the central
role of Rab7 in endosomaltraffic and summarize the studies focusing
on the participation of Rab7 in disease pathogenesis. The
underlyingmechanism governed by Rab7 and its partners will also be
discussed.
Key words: disease, endocytosis, membrane trafficking, pathogen
infection, Rab7, virus
INTRODUCTION
The Rab proteins belong to the Ras small GTPase superfam-ily.
During the past two decades, a large amount of literaturehas
addressed the properties and functions of the Rab proteinsand
established Rab GTPases as master regulators in membranetrafficking
[1–5]. Rab exerts its function through the GTPasecycle. Newly
synthesized Rab is recognized by REP (Rab es-cort protein) and
transferred to RabGGT (Rab geranylgeranyltransferase) for
prenylation, the prenylated Rab then goes on tothe GTPase cycle. In
the cytosoplasm, GDP-bound Rab is as-sociated with GDI (GDP
dissociation inhibitor), and GDF (GDIdisplacement factor) recruits
Rab to the membrane where GEF(guanine-nucleotide-exchange factor)
converts it into the GTP-bound active form, which interacts with
downstream effectors toexert its biological functions. GTP
hydrolysis of Rab convertsit back into the GDP-bound form, which is
generally facilitated
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Abbreviations used: BCV, Brucella-containing vacuole; BMDC,
bone-marrow-derived cell; CMT2B, Charcot–Marie–Tooth syndrome type
2B; DENV, Dengue virus; EEA1, early endosomeantigen 1; EGF,
epidermal growth factor; EGFR, EGF receptor; ER, endoplasmic
reticulum; ESCRT, endosomal sorting complex required for transport;
FSD, functional secretory domain;GAP, GTPase-activation protein;
GDI, GDP dissociation inhibitor; GDF, GDI displacement factor; GEF,
guanine-nucleotide-exchange factor; HOPS, homotypic fusion and
protein sorting;HPS, Hermanskey–Pudlak syndrome; HSAN, hereditary
sensory and autonomic neuropathy; Lamp, lysosome-associated
membrane protein; LDL, low-density lipoprotein;MVB, multivesicular
body; NGF, nerve growth factor; NPC, Niemann–Pick type C; OSBP,
oxysterol-binding protein; ORP1L, OSBP-related protein 1; PI3K,
phosphoinositide 3-kinase;PV, parasitophorous vacuole; RabGGT, Rab
geranylgeranyl transferase; RB, ruffled border; RBG-3, RabGAP
initially supposed to target Rab3; REP, Rab escort protein; RIDα,
receptorinternalization and degradation α; RILP, Rab7-interacting
lysosomal protein; SCV, Salmonella-containing vacuole; SFV, Semliki
Forest virus; Sif, Salmonella-induced filament; SLSD,sphingolipid
storage disease; SNX1/2, sorting nexin 1/2; TrkA, tropomyosin
receptor tyrosine kinase A; TRP, tyrosinase-related protein; UVRAG,
UV-irradiation resistance-associatedgene product; VEEV, Venezuelan
equine encephalitis virus; (h)Vps, (human) vacuolar protein
sorting; VSV, vesicular stomatitis virus.1To whom correspondence
should be addressed (email [email protected]).
by GAP (GTPase-activation protein). It has been indicated
thatRab proteins regulate not only membrane trafficking, but also
cellsignalling, cell growth, cell survival and development [6,7].
Rabproteins and their associated regulators or effectors have
beenimplicated in many diseases, such as cancer, pigmentation
dis-order, neuropathy and lipid metabolism disorders. Genetic
muta-tions and abnormal expression of Rab proteins or their
partnersare closely linked to disease pathogenesis [8–13].
Furthermore,pathogens usually hijack Rab-mediated trafficking
machineriesin host cells for infection and survival [10,14].
Therefore it willbe very useful to develop therapeutic strategies
targeting Rab ormodulating Rab-mediated membrane traffic [15].
For the Rab family of GTPases, approx. 70 members have
beenidentified in mammals. Rab7 is one of Rab proteins which
hasbeen investigated extensively. The extensive studies have
revealedthat Rab7 is a central factor in endosomal membrane
traffick-ing. Trafficking disorders, resulting from mutation or
dysfunc-tion of Rab7, can cause human diseases, and the
Rab7-mediated
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M. Zhang and others
membrane traffic process is linked to pathogen infection
andsurvival. In the following sections, we give a brief review
onthe functions of Rab7, summarize the involvement of Rab7
indisease pathogenesis and discuss the possible underlying
mech-anisms that are regulated by Rab7.
RAB7: CENTRAL ROLES IN THEENDOCYTIC PATHWAY
Rab7 is associated primarily with late endosomal structures,
andperhaps it is the only lysosomal Rab protein found to
date[16–20].The functions of Rab7 have been investigated
extensively. Fenget al. [21] indicated that the dominant-negative
mutants Rab7-T22N and Rab7-N125I blocked trafficking of the VSV
(vesicularstomatitis virus) G protein from the early endosome to
the lateendosome, without affecting its internalization from the
surface.In addition, the Rab7 mutants caused accumulation of
cathepsinD and the cation-independent mannose-6-phosphate receptor
inearly endocytic compartments, and inhibited the maturation
pro-cess of cathepsin D [22]. Vitelli et al. [23] examined the
effects ofRab7 on degradation of internalized LDLs (low-density
lipopro-teins) and found that dominant-negative forms of Rab7
inhibitedLDL degradation. These studies conclude that Rab7 serves
as akey factor in regulating transport of lysosome-destined
enzymesand internalized surface proteins to the lysosome through
theendocytic pathway.
It has been observed that Rab proteins act in concert withtheir
special tethering complexes to determine a unique mem-brane
identity, which generates various Rab-defined membranedomains
[2,4,24,25]. Within the endocytic pathway, many Rabproteins
localize to endocytic compartments: Rab4, Rab5, Rab11,Rab22 and
Rab25 are primarily associated with the early and re-cycling
endosomes [26–30]; Rab9 and Rab7 are localized to lateendosome
[31,32]. Rab7 is additionally localized to the lyso-some and was
thus characterized also as a lysosome-associatedRab protein [16].
Rab5 and its effectors, rabaptin-5, Rabex-5, EEA1 (early endosome
antigen 1), Rabenosyn-5, hVps34(human vacuolar protein sorting
34)/p150 may be defined as anearly endosomal membrane domain [33].
Rab4 and Rab11 havebeen shown to associate with the exocyst complex
at the recyc-ling endosomal membrane [34]. Rab7 and its effectors
are emer-ging to generate Rab7-defined membrane domains, playing
cent-ral roles in the late endocytic pathway (Figure 1).
Rab7-definedmembrane domains include late endosome, intermediate
hybridsof late endosomes–lysosomes, and the lysosome. Rab7
regulateslate endosomal membrane fusion and trafficking mediated by
atethering complex, which is carried out by the HOPS
(homotypicfusion and protein sorting; also refers to class C Vps
protein)complex. The HOPS complex consists of Vps11, Vps16,
Vps18,Vps33, Vps39 and Vps41. Vps39 binds to Rab7 and exhibits
GEFactivity for Rab7. Vps33 is a munc-1-like protein, which can
as-sociate with the endosomal SNARE (soluble
N-ethylmaleimide-sensitive fusion protein-attachment protein
receptor) protein to
regulate membrane fusion, thus Rab7 interacts with the
HOPScomplex and is recruited to the endosomal membrane to
regulatevesicle fusion [this process may also require
phosphoinositidesregulated by PI3K (phosphoinositide
3-kinase)/hVps34] [20,35–39]. The distribution and movement of the
late endosome/lyso-some is regulated by interaction of
Rab7—RILP–dynein–dynactin (where RILP is Rab7-interacting lysosomal
protein)[40,41].
Rab5-defined early endosomal membrane domains and Rab7-defined
late endosomal/lysosomal membrane domains do notwork separately,
but sequentially and dynamically to co-operatein the endocytic
pathway. Along the endocytic pathway, cargosare internalized from
the plasma membrane and transported tothe early endosome. At the
early endosome, cargos are sortedto different destinations: the
recycling endosome, the late endo-some and lysosome or the Golgi
apparatus (Figure 1), in which theRab cascade determines the unique
trafficking pathway [24,42].Membrane trafficking from the early
endosome to the late endo-some is determined by the recruitment of
Rab5 to earlyendosomes and, sequentially, acquisition of Rab7
followed byloss of Rab5 in the late endosomes. By employing
live-cell ima-ging technology, Rink et al. [38] observed the
conversion of Rabfrom Rab5 into Rab7 in endosomal membrane dynamics
duringthe transport from the early endosome to the late endosome.
Thedissociation of Rab5 and subsequent recruitment of Rab7
wereregulated by the HOPS complex. The HOPS complex may play
acritical role in this Rab cascade, since it is also an effector of
Rab5GTPase [43]. The sequential action of Rab5 and Rab7 in
endo-cytosis and endosomal sorting/maturation was also observed
inXenopus oocytes [44] and in axonal retrograde transport in
neur-ons [45]. Rab7, working co-operatively with Rab5, was
invest-igated in the recruitment of the retromer complex
[comprisingSNX1/2 (sorting nexin 1/2), Vps26, Vps29 and Vps35].
Theinteraction between Rab7 and the retromer complex has
beenstudied in the protozoan parasite Entamoeba histolytica
[46].Recently, the works by Rojas et al. [47] offered a possible
mech-anism for Rab5 and Rab7 to regulate retromer recruitment
andfunction. In this model, Rab5 interacted with PI3K and
recruitedSNX1/2 to membrane, whereas Rab7 recruited the retromer
corecomplex Vps26–Vps29–Vps35 through direct interaction withVps26.
The following interaction of SNX1/2 with Vps26/29/35mediates cargo
transport. Unexpectedly, the role of RILP in thisprocess was not
examined, and the HOPS complex may alsoplay a role in this
regulation. The involvement of Rab7 in ret-romer regulation
suggests that Rab7 also participates in retro-grade transport
between the endosomes and the Golgi apparatus.
The functions of Rab7 are regulated via the GTPase cycle andits
partners, including upstream regulators and specific down-stream
effectors, as shown in Figure 2. So far, there are noupstream
regulators, such as REP, RabGGT, GDI or GDF, identi-fied
specifically for Rab7, and Rab7 may share these common reg-ulators
with other Rab proteins. For example, Rab7 prenylationis regulated
by REP-1 [48]. Similar to other GTPases, Rab7 mayhave its specific
GAP and GEF. The yeast protein Gyp7p and itsmammalian homologue
TBC1D15 [a TBC (Tre2/Bub2/Cdc16)-domain-containing protein] were
identified as GAPs for Ypt7
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Rab7 in membrane trafficking and disease
Figure 1 Rab7 plays central roles in the late endosomal traffic
pathwayRab5 interacts with tethering complex (Rab5ex5, Rabaptin5,
Rabenosyn5 and EEA1) to regulate early endosomal traffick-ing; Rab4
and Rab11 associate with the exocyst to regulate recycling traffic
from the recycling endosome to the plasmamembrane; Rab7 interacts
with the HOPS complex and its various effectors to regulate
membrane traffic from the earlyendosome to the late endosome, and
from late endosome to the lysosome. See the text for further
details.
Figure 2 Regulation of Rab7 GTPase and interaction of Rab7
witheffctorsGDP-bound Rab7 can be converted into the GTP-bound
active form bya GEF (such as the HOPS complex), which interacts
with downstreameffectors to exert its biological functions. GAPs
(such as GYP7) facilitateGTP hydrolysis of Rab7 and convert it back
into the GDP-bound form.
and Rab7 respectively [49,50]. The HOPS complex exhibits
GEFactivity for Rab7 [37,38].
As shown in Table 1, Rab7 interacts with multiple down-stream
effectors. RILP is one of the well-studied Rab7 down-stream
effectors; the Rab7–RILP interaction is a crucial mechan-ism in
regulating endosomal traffic and biogenesis of late
endo-somal/lysosomal compartments [40,51]. Overexpression of
RILP
caused enlarged Rab7-containing late endosomes/lysosomeswith a
peri-nuclear distribution. The truncated form of RILPalso impaired
endosomal transport of EGFR (epidermal growthfactor receptor) and
LDL receptors [40]. Further investiga-tion revealed that Rab7
regulates lysosomal movement towardsthe MTOC
(microtubule-organizing centre) through RILP tointeract with the
minus-end-directed motor protein dynein–dynactin complex, with the
participation of another Rab7-interacting effector ORP1L [OSBP
(oxysterol-binding protein)-related protein 1] [41,52]. RILP can
also interact with Vps22and Vps36 to regulate the late endosomal or
MVBs (multivesi-cular bodies) degradation pathway [53,54]. Other
effectors forRab7 have also been described (Table 1). Rabring7
(Rab7-interacting RING-finger protein) is involved in EGF
degrada-tion as an E3 ligase [55]. PI3K/hVps34/p150 forms
complexeswith Rab7, suggesting that Rab7 may also regulate PI3K
activ-ity and membrane trafficking from the early endosome to
thelate endosome [56]. Rab7 can bind to the proteasome α-sub-unit
XAPC7 and recruit it to the late endosome. XAPC7 mayserve as a
negative regulator for Rab7, since overexpression ofXAPC7 impairs
EGFR-mediated endocytosis, which can be res-cued by expressing
wild-type Rab7 [57]. Rab7 directly interactswith small GTPase Rac1
to regulate the formation of RBs (ruffledborders) in osteoclasts
[58]. Collectively, Rab7 interacts withmultiple effectors and
participates in multiple biological events.
Rab7 plays a central role, not only in endosomal traffic,but
also in many other cellular and physiological events, suchas
growth-factor-mediated cell signalling,
nutrient-transportor-mediated nutrient uptake, neurotrophin
transport in the axonsof neurons and lipid metabolism. In addition
to the normal en-docytic traffic pathway, Rab7 is involved in
regulation of some
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M. Zhang and others
Table 1 Partners interacting with Rab7 in mammalian cells
Partner Partner function Reference
RILP Rab7-interacting lysosomal protein involved in late
endosomal/lysosomalmorphogenesis; regulates vesicle transport
through interaction withdynein–dynactin motor complex.
[40,41,51,52]
Rabring7 Rab7-interacting RING-finger protein; as a E3 ligase
which can ubiquitinate itselfand regulate EGFR degradation.
[55]
HOPS complex Homotypic fusion and vacuole protein sorting
complex, comprising VPS-11, -16,-18, -33, -39 and -41. A tethering
complex that regulates the endosomalmembrane fusion. VPS39 serves
as a GEF for Rab7.
[20,35–39]
Retromers The core retromer complex VPS26–VPS29–VPS35 interacts
with Rab7 throughVPS26 directly binding to Rab7; regulates the
retrograde transport fromendosomes to trans-Golgi network.
[46,47]
ORP1L OSBP (oxysterol-binding protein)-related protein; required
for activation ofdynein–dynactin motor, together with Rab7, RILP
and βlll spectrin; regulateslate endosome/lysosome organization and
late endocytic transport.
[52]
XAPC7 Proteasome α-subunit XAPC7 (PSMA7, HSPC, RC6-1, and C6-I
in mammals);overexpression of XAPC7 decreases late endocytic
transport.
[57]
Rac1 Ras-like small GTPase that regulates cytoskeleton
organization; Rab7 interactswith Rac1 to regulate RB formation in
osteoclasts.
[58]
Pleckhm1 Pleckstrin homology domain-containing family M (with
RUN domain) member 1;functions in vesicular transport in the
osteoclast.
[103]
hVPS34/p150 Human type III PI3K and adaptor regulating endosomal
trafficking and cellsignalling by producing
phosphatidylinositol-3-phosphate; Rab7 regulates theactivity of
hVPS34.
[56]
REP-1 Rab escort protein 1 that presents Rab7 to rab
geranylgeranyl transferase. [48]TrkA Receptor-tyrosine kinase A of
NGF; Rab7 interacts with TrkA controlling the
endosomal trafficking and neurite outgrowth signaling of
TrkA.[76]
TBC1D15 TBC (Tre-2/Bub2/Cdc16) domain-containing protein
homologue of GYP7p, a GAPfor Ypt7p in yeast; serves as a GAP for
Rab7.
[49,50]
specialized endosomal membrane trafficking, such as maturationof
melanosomes, pathogen-induced phagosomes (or vacuoles)and
autophagosomes. In the following sections, we will describesome
diseases or physiological disorders caused by mutations
ordysfunction of Rab7, and how Rab7 and its partners are engagedin
infectious diseases caused by microbial pathogens or viruses.
DISEASES CAUSED BY MUTATIONSOR DYSFUNCTION OF RAB7
Rab proteins are master regulators of membrane trafficking.
Stud-ies have linked Rab proteins and Rab-regulated traffic to
manydiseases [10,13]. For examples, genetic defects in Rab27a
andits partner Myo5a cause Griscelli syndrome [59]; mutations inthe
upstream regulators of Rab, REP, RabGDI and RabGGT, arelinked to
the renal degeneration disease choroidaermia, X-linkedmental
retardation and HPS (Hermanskey–Pudlak syndrome) re-spectively
[60–62]; abnormal expression of Rab25 is associatedwith the
development of ovary and breast cancer [63]. A num-ber of studies
have indicated that Rab7 is another important Rabinvolved in
disease pathogenesis. Mutations in Rab7 gene ordysfunction of Rab7
and Rab7-interacting effectors may causediseases or physiological
disorders (Table 2).
Rab7 in neuropathySeveral Rab proteins are expressed in neurons
and glia, and someof them are closely related to neurological
functions [64]. Thereare reports showing that defects of Rab5 and
Rab7-regulatedlate endocytic traffic are related to neurological
diseases, such asAlzheimer’s disease and Down’s syndrome [65]. The
direct evid-ence that Rab7 is involved in neuropathy comes from the
studieson CMT2B (Charcot–Marie–Tooth syndrome type 2B). Muta-tions
in Rab7 are well characterized as genetic defect markers forCMT2B,
which is part of a group knowns as the HSNs [hereditarysensory
neuropathies; also referred as HSANs (hereditary sens-ory and
autonomic neuropathies)]. Patients suffering this defectexhibit
progressively neurological disorders with clinical symp-toms of
distal sensory loss, muscle weakness and foot ulcerations[66–69].
So far, four mutations in Rab7 have been identified infour
different families with CMT2B, and all mutations occur inthe
conserved amino-acid residues adjacent to the switch II regionin
the C-terminal part of Rab7, including the mutations L129F,K157N,
N161T and V162M [70–73].
Recently, the underlying mechanisms for CMT2B due to
Rab7mutations have been investigated. Spinosa et al. [74] studied
thebiochemical and functional properties of three Rab7
mutants,Rab7-L129F, Rab7-N161T and Rab7-V162M, and found all
threemutant forms exhibited lower GTPase activity than the
wild-typeform and had a preference for GTP binding, indicating the
mu-tant forms of Rab7 are more activated than wild-type Rab7,
which
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Table 2 Diseases that may be related to defects in Rab7 or its
partnersARC, arthrogryposis-renal dysfunction-cholestasis; MEF,
mouse embryonic fibroblast; RNAi, RNA interference.
Disease Patho-mechanism related to Rab7 Reference
Neurological disease
CMT2B Genetic mutations in Rab7 gene at L129F, K157N, N161Tand
V162M.
[70–73]
Alzheimer’s disease and Down’s syndrome Late endocytic traffic
defects possibly regulated by Rab7and Rab5.
[65]
Cancer and cell survival
Thyroid adenomas Rab7 is overexpressed by cAMP stimulation.
[80]
Diffuse peritoneal malignant mesothelioma Rab7 is overexpressed.
[79]
Growth-factor-independent survival Inhibition of Rab7 sustains
surface nutrient transportorupon growth-factor depletion.
[7,81]
Transformation of p53−/− MEFs Inhibition of Rab7 co-operates
with E1A and in theabsence of p53.
[82]
Cell apoptosis RNAi of Rab7 and its down stream effectors:
componentsof HOPS complex.
[83,84]
Lipid trafficking disorder
NPC disease Dysfunction of Rab7 results in accumulation
ofsphingolipids and cholesterol in late endosomes.
[91–93]
Adult-onset obesity Involvement of Rab7 in tub-1 pathway through
interactionwith the partner of tub-1, RBG-3.
[97,98]
Osteoclast function Rab7 regulates polarization of osteoclasts
and vesiculartraffic in osteoclasts, possibly through interaction
withRac1 and Plekhm1.
[58,102,103]
Others
HPS and other melanogenic diseases Dysfunction of the effectors
of Rab7: components of HOPscomplex.
[105–112]
ARC syndrome Genetic mutation in Rab7 down stream effector
Vps33b. [113]
is similar to the constitutively active mutant Rab7-Q67L, and
allthe mutants can interact with the downstream effector RILP
[74].Similar properties were also studied on the Rab7-K157N
mutant[73]. The results suggest that activated Rab7 and
Rab7-regulatedendocytic traffic processes may be responsible for
CMT2B neuro-pathies. Interestingly, another type of HSAN, HSAN-1 is
due tothe mutation in the gene for SPTLC1 (serine
palmitoyltrans-ferase long chain), which is involved in
sphingolipid synthesis[69,75]. Since Rab7 is also involved in the
transport of sphingol-ipids, CMT2B and HSAN-1 may potentially share
an overlappingpathogenesis mechanism.
Rab7 regulates membrane trafficking in neuronal cells. InPC12
cells, Rab7 can associate with the NGF (nerve growthfactor)
receptor TrkA (tropomyosin receptor tyrosine kinase A)at endosomes.
Inhibiting Rab7 activity resulted in accumula-tion of TrkA in the
endosome and potentiated NGF-stimulatedsignalling of TrkA to induce
neurite outgrowth [76]. Axonaltransport contributes long-range
communication in neurons andis essential for the survival and
differentiation of neurons. UsingTeNT Hc (atoxic fragments of the
tetanus neurotoxin) as a marker,which shares the same retrograde
pathway as neurotrophins andtheir receptors, Deinhardt et al. [45]
demonstrated that functionalRab7 is required for retrograde
transport of the neurotrophin re-ceptor [45]. The above data
suggest that dysfunction of Rab7and the disruption of
Rab7-regulated membrane traffic may in-hibit neuron growth or
promote apoptosis due to nutrient deficit,causing neurodegenerative
diseases. Rab7 controls endosomal
trafficking of TrkA and TrkA-mediated neuritogenic
signalling,and also regulates axonal retrograde transport of
neurotrophin.These results may also partly explain how
Rab7-regulated mem-brane traffic is responsible for CMT2B and other
neurodegen-erative diseases. The reason why mutations of
ubiquitouslyexpressed Rab7 have a more profound effect on
peripheral neur-ons, with little effects on other tissue/organs,
may be due to therequirement of more-tightly regulated membrane
trafficking inneurons.
Rab7 in cancer and cell survivalAberrant endocytosis and altered
lysosomal function result in de-fective growth-factor transport and
unbalanced levels of surfaceproteins, such as integrins and
E-cadherin, leading to tumori-genesis and cancer metastasis
[77,78]. Rab GTPases, as masterregulators in membrane traffic, are
proved to be involved in can-cer development [11]. Rab25 is a
well-established tumorigenesis-associated Rab and is highly
homologous to Rab11, and endogen-ously overexpressed in most
ovarian and breast cancer samples ina constitutively active form,
which is unique among Rab proteins.Cheng et al. [63] provided data
indicating that overexpressionof Rab25 promotes cell
transformation, inhibits apoptosis andinduces tumour progression,
probably through the PI3K/AKTsignalling pathway. Rab25 may also be
related to other cancersuch as OC/PPC (ovarian/primary peritoneal
serous carcinoma)and prostate cancer [79].
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The results from Croizet-Berger et al. [80] showed thatthyroid
hormone production was regulated by Rab5a and Rab7.cAMP stimulation
elevated the expression of Rab5a andRab7 in adenomas, linking Rab7
to the formation of benignthyroid autonomous adenomas [80].
Davidson et al. [79] alsofound Rab7 is overexpressed in DMPM
(diffuse peritoneal ma-lignant mesothelioma). In addition, v-Src
induces activation ofRab7, which may be related to
epithelial-to-mesenchymal trans-ition during tumour progression
[77]. Studies by Edinger et al.[81,82] indicate that Rab7 is
involved in a cell survival path-way. Upon growth-factor depletion,
Rab7 down-regulates surfacenutrient transporters through endocytic
degradation, preventinggrowth-factor-independent survival, but
inhibition of Rab7 sus-tains surface nutrient transporters, thus
promoting long-term cellsurvival, which is dependent on the AKT
survival signalling path-way. Furthermore, Edinger and colleagues
[81,82] demonstratedthat inhibition of Rab7 co-operated with the
adenoviral E1Aprotein to promote transformation of p53−/− MEFs
(mouse em-bryonic fibroblasts), thus Rab7 was proposed to act as a
potentialtumour suppressor (reviewed in [7]). However, there is
insuffi-cient evidence to conclude that Rab7 functions as a tumour
sup-pressor. As mentioned above, Rab7 is actually overexpressed
insome cancer cells or tissues, as described previously [79,80],
andthe transformation effects of dominant-negative Rab7 requiredthe
crucial help of the E1A protein and the absence of p53 in
thestudies by Edinger and colleagues [81,82], and these studies
werecarried out under nutrient starvation condition which may
differslightly from the environmental conditions for tumorigenesis
thatare usually rich in growth factors. Lackner et al. [83]
providedanother view on the function of Rab7 in apoptosis.
Inhibitingthe upstream regulator RabGGT prominently induces
apoptosisof germ cells in Caenorhabditis elegans and mammalian
cancercells. Lackner et al. [83] also examined the effects of
knockdownof Rab5, Rab7 and components of the HOPS complex by
RNAinterference in C. elegans, and found that knockdown of both
Rabproteins promoted germ cells apoptosis. In addition, knockdownof
the HOPS complex (comprising Vps11, Vps16, Vps18, Vps33and Vps39)
also induced apoptosis, suggesting that Rab7 and theRab7-regulated
pathway are involved in suppressing apoptosis[83]. In disagreement
to the conclusion by Lackner et al. [83],Kinchen et al. [84] got
similar results from knockdown of Rab5,Rab7 and the HOPS complex in
C. elegans, but they examinedthe increase of apoptotic cells for
loss of ‘cleaning’ functions bydefective phagocytosis. Taken
together, the underlying mechan-ism for cancer, cell survival and
apoptosis regulated by Rab7 isstill not yet understood.
Rab7 is also emerging as a regulator for the autophagic
path-way, another mechanism for cell death and survival, which is
re-lated to many diseases, such as cancer and heart failure
[85,86].The autophagic process is initiated by engulfment of
cytoplas-mic materials into a unique membrane (phagophore) to form
anautophagosome; the autophagosome then undergoes maturationthrough
fusion with endosomal vesicles and lysosomes to forma
lysoautophagosome, in which materials are degraded to pro-vide
nutrients and energy for cell survival under nutrient de-pletion.
The late autophagic process is similar to late endocytic
fusion, and the mechanism for regulating autophagosome
mat-uration is becoming clear, and Rab7 has been shown to be amajor
factor in governing the transport and fusion events
duringmaturation of autophagosome [87,88]. Furthermore, Rab7 is
reg-ulated by Beclin1, a tumour suppressor able to induce
autophagy,through the Beclin1–UVRAG–HOPS complex–Rab7
interactioncascade (where UVRAG is UV-irradiation
resistance-associatedgene product), since the UVRAG and the HOPS
complexes areeffectors for Beclin1 and Rab7 respectively [89].
Rab7 in lipid trafficking disordersSphingolipids associate with
cholesterol in the plasma mem-brane to form unique lipid rafts,
which play important roles inmembrane organization, cell signalling
etc. [90]. Upon stimula-tion, sphingolipids and cholesterol can be
internalized througheither clathrin-dependent or caveolin-mediated
endocytosis intolate endosomes. In the late endosome, the
sphingolipids can befurther transported to the lysosome for
degradation, or the Golgiapparatus or other organelle;
mis-regulation of these transportevents results in accumulation of
sphingolipids in late endo-somes and causes SLSDs (sphingolipid
storage diseases) [91].NPC (Niemann–Pick type C) disease is a well
known SLSD,which is caused by mutations in the NPC-1 and NPC-2
genes,characterized by accumulation of sphingolipids and
cholesterolin the late endosome due to a lipid traffic jam. There
is evid-ence suggesting that Rab7 is linked to NPC disease [92].
Zhanget al. [93] provided data demonstrating that NPC-1 protein
isassociated with the Rab7-containing late ensosome. Choudhuryet
al. [94] investigated lipid trafficking in NPC cells. Their
res-ults showed that the fluorescent glycosphingolipid,
BODIPY®–lactosylceramide, is targeted to the Golgi in normal human
skinfibroblast cells, and dominant-negative mutants of Rab7 andRab9
impaired the Golgi targeting. Furthermore, overexpressionof
wild-type Rab7 or Rab9 (but not Rab11) can reduce cho-lesterol
accumulation in NPC cells and restore the traffickingof
BODIPY®–lactosylceramide to the Golgi, which indicates anovel
potential therapeutic strategy for this disease [94]. How-ever,
Lebrand et al. [95] found that overexpressing Rab7 increasedthe
accumulation of cholesterol and reduced late endosomal mo-bility,
which is not consistent with the study by Choudhury et al.[94].
This difference may be due to the different cell types thatwere
used, but more work is required to reveal the underlyingmechanisms
for the involvement of the regulation of Rab7 inNPC disease.
Intriguingly, accumulation of cholesterol affects APP (amyl-oid
precursor protein) processing by inhibiting β-secretase,
butenhancing γ-secretase, to produce both Aβ40 (amyloid β-peptide
40) and Aβ42, and alters presenilin localization to Rab7-positive
late endosomes [96]. As discussed above, cholesterolaccumulation is
also regulated by Rab7 in NPC disease cells,suggesting that Rab7
links lipid trafficking disorders to neurode-generative
disease.
Rab7 is also implicated in the tub-1 pathway to regulate
fatstorage. tub-1 is a transcription factor, and mutation in this
generesults in adult-onset obesity, insulin resistance and
progressiveneurosensory deficits [97]. Mukhopadhyay et al. [98]
found that
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tub-1 interacts with the RBG-3 (RabGAP initially supposed
totarget Rab3) protein, which serves as a GAP for Rab7. RNA
in-terference of Rab7 can reduce fat storage in C. elegans,
proposinganother role of Rab7 in lipid metabolism through
interaction withRBG-3.
Although genetic defects in Rab7 have not been identified
inlipid metabolism disorder, the Rab7 gene is up-regulated by
acholesterol-rich diet in the liver and atherosclerotic plaques
ofarteries [99], supportive for a role of Rab7 in diseases related
tolipid trafficking disorders. However, the underlying
mechanismsfor the regulation of Rab7 in lipid trafficking remain to
be elucid-ated. In particular, little is known about the
interacting partnersfor Rab7 that are involved in these
regulations. Investigationsof the interaction between Rab7 and
ORP1L (a member of thehuman OSBP family involved in cholesterol and
sphingomyelinmetabolism) may provide one of the starting clues for
studyingthese mechanisms [100].
Rab7 in osteoclast functionBone-resorbing osteoclasts are highly
polarized with distinctmembrane domains: SZ (sealing zone), RB, BD
(basolateral do-main) and FSD (functional secretory domain). The
resorptionprocess includes: resorption of broken bone matrix in
RBs, tran-scytosis of degraded materials and secretion in FSDs.
Disrup-tion of bone resorption results in osteopetrosis, but
excessiveresorption induces osteoporosis. The RB is a unique
structurethat is similar to late endosomes/lysosomes and is
character-ized by acidic environments, association with Lamp1
(lysosome-associated membrane protein 1) and Lamp2 etc. The RB is
cru-cial for proper bone resorption. The function of the RB
dependson vesicular trafficking regulated by Rab GTPases [101],
andRab7 is one of most important Rab GTPases in regulating
osteo-clast function. Rab7 is found highly expressed in
bone-resorbingosteoclasts and predominantly localized to the RB.
Decreasingexpression level of Rab7 disrupted the polarization of
osteoclastsand impaired bone resorption in vitro [102]. The more
profoundregulation mechanisms were investigated more recently. Sun
et al.[58] identified Rac1 as a Rab7-interacting effector, and the
Rab7–Rac1 interaction as being regulated by the formation of RBs in
os-teoclasts. Furthermore, the Rab7–Rac1 interaction suggests
thatRab7 regulates membrane trafficking, which is orchestrated
bythe interactions between RLIP–dynein–dynactin–microtubulesand
Rac1–actin filaments. In addition, a
pleckstrin-homology-domain-containing protein, Plekhm1, was also
characterized as apotential effector for Rab7; Plekhm1 association
with Rab7 is de-pendent of the prenylation of Rab7. Loss of
function of Plekhm1is responsible for osteopetrosis [103]. As Rab7
plays importantroles in osteoclasts, the modulation of Rab7
activity may be de-veloped into new therapeutic strategy for
treating osteopetrosisor osteoporosis.
Rab7 in the pathogenesis of other diseasesThe melanosome is an
LRO (lysosome-related organelle), andtyrosinase and TRPs
(tyrosinase-related proteins) are melanomalmembrane-bound proteins
that are only expressed in melano-cytes [104]. Hirosaki et al.
[105] found that a dominant-negative
mutant of Rab7 impaired the vesicular transport of tyrosinase
andTRPs from the Golgi to the melanosome, suggesting that Rab7is
involved in the biogenesis of melanosomes. However,
geneticmutations in Rab7 were not observed in diseases caused by
abnor-mal melanogenesis, such as OCAs (oculocutaneous
albinisms)[106]. However, the HOPS complex, which serves as an
effectorand a GEF for Rab7, plays significant roles in
melanogenesis, anddysfunction of the HOPS complex results in
aberrant pigmenta-tion, albinisms and immuodeficiency disease, such
as HPS; forexample, reduced expression of Vps11 causes less
pigmentationin medaka fish [107], defects in Vps18 and Vps39 induce
hypo-pigmentation in zebrafish [108,109], Vps16 is required for
endo-somal trafficking and pigment-granule biogenesis in
Drosophila[110], and the mouse model exhibiting the HPS phenotype
resultsfrom a mutation in Vps33a [111]. Furthermore, another
com-ponent of the HOPS complex, Vps41, regulates alkaline
phos-phatase transport through interaction with the δ-subunit of
theAP-3 adaptor, which is well characterized as being
associatedwith melanogenic diseases [112]. Gissen et al. [113]
reportedthat mutation in Vps33B (Vps33a isoform) causes a severe
auto-somal recessive multisystem disorder, which is known as
ARC(arthrogryposis-renal dysfunction-cholestasis) syndrome. In
con-clusion, Rab7 is likely to be involved in melanogenic
diseasesthrough interaction with its partners, such as the HOPS
complex.
RAB7 IN INFECTIOUS DISEASES
In addition to diseases resulting directly from dysfunctionof
Rab7 or its partners, Rab7 and its partners are import-ant factors
in the pathogenesis of infectious diseases causedby
micro-organisms, in which Rab7 is a key regulator in theprocess of
phagosome maturation [114–118]. When microbialpathogens are
engulfed by host cells (e.g. macrophages), theyreside in a
membrane-bound vacuole or phagosome; the va-cuole/phagosome then
fuses with late endosome to form aphagolysosome, and within the
phagolysosome the pathogensare degraded. However, many microbial
pathogens have evolvedelaborate mechanisms to evade degradation and
therefore sur-vive within the host cells. The modulation of the
function ofRab GTPases is one of the important strategies for the
infec-tion and survival of microbial pathogens [14]. Rab7 is
involvedin pathogenesis of infectious diseases and has been
examinedin divergent microbial pathogens (Table 3), including
bacteria,protozoan, fungi and viruses.
Bacteria and other microbial pathogensBacteria infect host cells
through phagocytosis; Rab7, togetherwith its partners (e.g. RILP),
are essential factors in regulat-ing the maturation of the
phagosome into a lysophagosome,which has been well studied
[119,120]. The roles of Rab7 or itspartners in bacterial infection
have been studied extensively forMycobacterium tuberculosis,
Mycobacterium bovis BCG,
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M. Zhang and others
Table 3 Rab7 in divergent pathogen infection and survival
Pathogen Rab7 involvement Reference
Bacteria
Mycobacterium bovis BCG Exclusion of Rab7 or RILP
inhibitsMycobacterium–phagosome maturation intophagolysosomes.
[121]
Mycobacterium tuberculosis Involvement of Rab7 in bacterial
phagosome maturationarrest.
[122]
Salmonella enterica Typhimurium SCV formation requires Rab7 and
RILP, but Sifs maturationis dependent of abolishing Rab7–RILP
interactionregulated by SifA.
[119,124–127,129]
Helicobacter pylori Rab7 and RILP regulate VacA-induced
vacuolation. [132,133]
Brucella abortus Dysfunction of Rab7 or RILP impairs BCV
maturation tosurvival and replication organelle.
[134]
Bacillus anthracis Rab7-T22N enhances sterne spore survival.
[135]
Staphylococcus aureus Not clear. [139]
Neisseria gonorrhoeae Exclusion of Rab7 and RILP on bacterial
phagosome inLamp1 and Lamp2 double-knockout cell.
[136]
Escherichia coli strain LF82 Bacteria survival acquires Rab7
function. [141]
Parachlamydia acanthamoebae Rab7 is involved in the endocytic
traffic of P.acanthamoebae.
[138]
Legionella pneumophila Phagosome maturation is arrested, despite
of acquisitionof Rab7.
[122]
Protozoan
Leishmania donovani Involvement of Rab7 in the biogenesis of
parasitophorousvacuoles.
[115]
Trypanosoma cruzi Dominant-negative Rab7 reduces infection.
[143,144]
Toxoplasma gondii Rab7 may regulate the maturation of
autophagosome-likevacuole induced by T. gondii.
[145]
Others
Aspergillus fumigatus Rab7 may regulate phagocytosis and
survival of conidia. [140]
Coxiella burnetii Rab7 participates in the biogenesis of C.
burnetii-inducedautophagosome-like vacuole.
[137]
Virus
Adenovirus serotype 7 (Ad7) Virus co-localizes with Rab7.
[155]
Influenza virus Dominant-negative Rab7 inhibits infection.
[156]
SFV Expression of Rab7-T22N results in accumulation of SFVsin
early endosomes and reduces virus entry.
[157]
SFV fus-1 Infection was inhibited by Rab7-T22N. [159]
VSV VSV entry was reduced by Rab7-T22N. [158]
HIV-1 Overexpression of Rab7 results in an almost
completeblockade of HIV-1 gene expression in trophoblasts.
[160]
DENV DENV matures in late endosomal compartments byacquisition
of Rab7 and loss of Rab5.
[162]
Pichinde virus Knockdown of Rab7 results in 80% reduction of
productionof viral proteins.
[164]
Recombinant adeno-associatedvirus type-2 (rAAV2)
Overexpression of Rab7 decreases rAAV2 transduction. [165]
Ebola virus Expression of Rab7-T22N inhibits entry of Ebola
viruspseudoparticles.
[166]
Group C adenovirus Rab7 may regulate viral life cycle
throughRILP–ORP1L–RIDα interaction.
[172]
VEEV Rab7-T22N significantly inhibits entry of virus;
VEEVinfection requires Rab7 in mosquito cells.
[158,170]
White-spot syndrome virus (WSSV)and yellow head virus (YHV)
inPenaeus monodo
Suppression of Rab7 inhibits viral infection. [168,169]
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Rab7 in membrane trafficking and disease
Salmonella enterica Typhimurium, Helicobacter pylori and oth-ers
(Table 3).
M. tuberculosis is the most virulent pathogen in human his-tory,
causing over 1 billion people to suffer from tuberculosis.Via et
al. [121] first established the phagosome-arrest model forpathogen
survival in host cells during M. bovis BCG infection,In this model,
two Rab proteins, Rab5 and Rab7, play key rolesin controlling
Mycobacterium phagosome maturation. The form-ation of
Mycobacterium-containing phagosomes requires Rab5;but selective
exclusion of Rab7 blocks phagosome fusion withlate endosomes, and
results in Mycobacterium-containing pha-gosome arrest in early
stage, and therefore Mycobacterium canescape degradation and
survive in host cells. The selective ac-cumulation of Rab5 and
exclusion of Rab7 defines the check-point in the mycobacterial
phagosome maturation process. In-terestingly, Clemens et al. [122]
found that M. tuberculosis andLegionella pneumophila phagosomes
still exhibited arrested mat-uration, despite acquisition of Rab7,
and phagosomes contain-ing live M. tuberculosis recruit even more
active Rab7 in HeLacells, and the authors [122] proposed that this
discrepancy waslikely due to using different cell types
(macrophages and epi-thelial cells), different bacteria species (M.
bovis BCG andM. tuberculosis) and different detection technologies.
Never-theless, subsequent investigations may provide a more
mechan-istic explanation for phagosome maturation arrest, even with
theacquisition of Rab7 to Mycobacterium-containing phagosomes.The
Rab7 downstream effector RILP is also required for phago-some
maturation; the results from Sun et al. [120] indicated thatM.
bovis BCG inhibited RILP recruitment, despite Rab7 acquis-ition by
the phagosome, therefore inhibiting phagosome matura-tion, in
addition, Rab7 (GDP-bound form) predominates in cellsinfected with
live M. bovis BCG, and the M. bovis BCG culturesupernatant contains
a factor that catalyses the GTP/GDP switchon recombinant Rab7
molecules. Previous studies [122] indicatedthat the modulation the
conversion of Rab5 into Rab7 is a crucialmechanism for
Mycobacterium-containing phagosome matura-tion arrest. A study by
Roberts et al. [118] revealed that Rab22a,an early endosomal Rab
protein, is also critical in regulating Rab7conversion on
phagosomes during M. tuberculosis infection, andRab22a knockdown in
macrophages via siRNA (small interferingRNA) enhanced the
maturation of phagosomes with live Myco-bacteria by increasing the
association of Rab7 with phagosomes.M. tuberculosis may actively
recruit and maintain Rab22a onits phagosome, thus inhibiting Rab7
acquisition and blockingphagolysosomal biogenesis [118]. Philips et
al. [123] reportedthat ESCRT (endosomal sorting complex required
for transport)factors (VPS28, TGS101 and VPS4 were examined in
[123]),as well as Rab7, restrict Mycobacterium smegmatis growthin
Drosophila and mammalian cells. Because RILP interactswith the
ESCRT II complex [53,54], Rab7 may regulateMycobacteria-containing
phagosome maturation through regu-lating ESCRT machineries in
Mycobacteria infection. Taken to-gether, Rab7 is involved in
Mycobacteria infection, which isregulated by other factors.
S. enterica Typhimurium is a facultative pathogen, which
in-vades various cell types, including epithelial cells and
macro-
phages. Infection experiments in vitro revealed that
Salmonellaresides within SCVs (Salmonella-containing vacuoles)
after en-tering into host cell. In SVCs, bacteria induce expression
of SPI-2(Salmonella pathogenicity island 2)-encoded TTSS (type III
se-cretion system) effector SifA. SifA regulates SCV maturationinto
Sifs (Salmonella-induced filaments), allowing for maximalspace for
bacteria replication; and Sifs will not fuse with lyso-somes,
permitting bacteria survival and replication. The rolesof Rab7 in
SCVs have been investigated. Merésse et al. [124]showed that Rab7
is associated with SCV, and Rab7 may controlthe biogenesis of SCVs
by recruiting lgps (lysosomal glycopro-teins) to SCVs, suggesting
that SCV maturation requires fusionwith late endosomal membranes
regulated by Rab7. Studies byBrumell et al. [125] indicated that
Rab7 was also present in Sifs,and expression of the
dominant-negative mutant Rab7-N125I in-hibited Sif formation. In
addition, overexpression of Rab7-N125Icaused a loss of SCV
integrity and increased Salmonella replica-tion in the cytosol
[126]. Drecktrah et al. [127] confirmed that theacquisition of
endosome/lysosome content by SCVs is Rab7 de-pendent using a
high-resolution live-cell-imaging approach. An-other study by
Harrison et al. [119] revealed that the maturationof SCVs and Sifs
is regulated by Rab7 and its effector RILP. Theinitial centripetal
displacement of the SCV is due to recruitmentof RILP by Rab7, which
may govern the centripetal move-ment of the SCVs through
interaction with dynein–dynactin com-plex. When Sifs are induced,
RILP is depleted, despite the pres-ence of Rab7. As a result, Sifs
extend towards the periphery. Inthe process of Sif formation, the
bacterial factor SifA is criticalfor disengaging of RILP from Rab7,
which may serve as an inter-action partner for Rab7. In summary,
although many Rab proteinsmay associate with SCVs or Salmonella
phagosome [128], Rab7is probably the most important Rab protein in
SCV biogenesis, inthat SCV maturation requires Rab7–RILP to
regulate SCV fusionwith late endosomal membrane to gain some late
endosomal com-ponents, such as Lamp proteins, cathepsin D and LBPA
(lyso-bisphosphatic acid), determining SCV and Sifs as special
struc-tures different from Mycobacterium–phagosome. Nevertheless,a
previous study by Hashim et al. [129] demonstrated that liveLSPs
(Salmonella-containing phagosomes) retain a significantamount of
Rab5, but selectively deplete Rab7 and Rab9, with aproperty similar
to Mycobacterium–phagosome, suggesting thatdifferent conditions in
vitro, such as different cell types, bacteriastrains etc., may give
rise to different outcomes.
H. pylori is another representative micro-organism that
pos-sesses a survival strategy through modulating Rab7 function to
es-cape degradation in host cells. In host cells, H. pylori
releases thetoxin VacA. VacA induces vacuolation, generating
enlarged andperi-nuclear-distributed Helicobacter-containing
vacuoles. Thisvacuole, containing the late endosomal markers Rab7,
Lamp1 andCD63, but not Rab5, mannose-6-phosphate receptor,
transferrinreceptor and cathepsin D [130], has been described as a
post-endosomal hybrid compartment, with both late endosomal
andlysosomal features [131]. Since the VacA-induced vacuoles
lackthe ability of degradation, bacteria can survive in this
specializedstructure. Rab7 was shown to be essential for the
biogenesis ofthe VacA-induced vacuoles [132]. The active Rab7-Q67L
mutant
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M. Zhang and others
enhances VacA-induced vacuolation, whereas Rab7-T22N
orRab7-N125I effectively inhibits vacuolation. Rab5 and Rab9have
less effect. In addition to the engagement of Rab7 in VacA-induced
vacuolation, the Rab7 effector RILP is also associatedwith the
VacA-induced vacuoles. RILP is thought to regulate largevacuole
formation and cellular distribution of the VacA-inducedvacuoles.
Furthermore, the interaction between Rab7 and RILPis important for
vacuolation, as the expression of mutant formsof RILP or Rab7 that
failed to bind each other impaired the form-ation of this unique
bacteria-containing vacuole [133]. Thesedata suggest that VacA
prevents the maturation of the Helicobac-ter-containing vacuole
into a bactericidal structure by retentionof Rab7 and RILP. How
VacA-induced vacuole maintains itsunique characteristics for
bacteria survival and whether VacA in-teracts with Rab7 or RILP (or
other Rab7 effectors) remain to beanswered.
The roles of Rab7 were also examined in phagocytosis ofother
microbial pathogens (Table 3). Brucella abortus invadeshost cells
and resides within BCVs (Brucella-containing vacu-oles). BCVs fuse
with the ER (endoplasmic reticulum)-derivedmembrane structure to
generate a replicative organelle. It hasbeen observed that both
Rab7 and RILP were recruited to theBCVs during BCV maturation.
Overexpression of the dominant-negative Rab7-T22N or RILP impaired
biogenesis of the ER-derived organelle and replication of bacteria
[134], suggestingthat BCV maturation requires interactions with
functional lateendosomal/lysosomal compartments. In phagocytosis of
Bacil-lus anthracis spores, expression of the dominant-negative
Rab7-T22N, which blocked lysosomal fusion, enhanced sterne
sporesurvival [135]. Exclusion of Rab7 and RILP on bacterial
pha-gosomes in a Lamp1/Lamp2 double-knockout cell infected
byNeisseria gonorrhoeae indicated that Rab7 is involved in the
mat-uration arrest of N. gonorrhoeae-containing phagosomes
[136].Rab7 and Rab7-Q67L localized to Coxiella
burnetii-inducedautophagosome-like vacuoles, suggesting that Rab7
participatesin the biogenesis of this pathogen-containing vacuole
[137]. Rab7may regulate Parachlamydia acanthamoebae trafficking
alongthe endocytic pathway [138], and is probably engaged in
thesurvival strategies by Staphylococcus aureus [139]. Rab7 mayalso
participate in regulating phagocytosis and the intracellu-lar fate
of conidia of the fungal pathogen Aspergillus fumigatus[140].
Interestingly, some bacteria, such as the Crohn’s
disease-associated adherent–invasive Escherichia coli strain LF82,
do notescape from the endocytic pathway, but undergo a normal
inter-action with the host endomembrane organelles, acquiring
Rab7function, and replicate within acidic and cathepsin D-positive
va-cuolar phagolysosomes [141]. The mechanisms for the
bacteriaescaping degradation are not clear.
In protozoa infection, wild-type Leishmania donovani
pro-mastigotes inhibit phagosome maturation due to impaired
re-cruitment of Rab7, prolonging bacterial survival in the mur-ine
macrophage cell line J774 [115]. Rab7 was found only inthe PVs
(parasitophorous vacuoles) of mature BMDCs (bone-marrow-derived
cells), and it was absent in immature BMDCs,suggesting an arrest of
their PV biogenesis at the stage of thelate endosome [142].
Trypanosoma cruzi invades cells through
the endocytic pathway where expression of dominant-negativeRab7
reduces infection, with the same effects found for Rab5and dynamin
[143]. In addition, T. cruzi down-regulates Rab7in T.
cruzi-infected cardiomyocytes [144]. Rab7 may also regu-late the
maturation of autophagosome-like vacuoles induced byToxoplasma
gondii; experiments inhibiting PI3K, Rab7, vacuolarATPase and
lysosomal enzymes revealed the vacuole/lysosomefusion event
mediates antimicrobial activity which is induced byCD40 [145].
In summary, Rab7 plays a central role in regulating phago-some
maturation when cells are infected by microbial patho-gens.
Microbial pathogens possess survival strategies governedby Rab7,
sometimes by employing Rab7 function (e.g. Salmon-ella) and
sometimes by excluding Rab7 function (e.g. Mycobac-terium). As
shown in Figure 3, microbial pathogens infect cellsthrough
phagocytosis and survive in host cells with a
similarphagosome-arrest strategy by manipulating the function of
Rabproteins. Pathogens enter host cells and reside in nascent
pha-gosomes with reduced acidification. This
pathogen-containingphagosome requires Rab5 GTPase to fuse with
early endosometo form early phagosome; the early phagosome then
fuses withlate endosome to form a phagosome, acquiring some late
endo-somal components, but usually fails to recruit Rab7 GTPase
orits partners, preventing phagosome maturation into phagolyso-some
and allowing pathogen survival in the arrested phagosome.Some
pathogen-containing phagosomes are also arrested by par-tial
acquisition of late endosomal components, including Rab7,and form a
late endosome/phagosome hybrid, which also cannotmature into a
bactericidal phagolysosome. The important roles ofRab7 in diseases
caused by micro-organisms suggest that modu-lation of Rab7 function
may be a potential treatment strategy.
VirusViruses infect cells and take over cellular machineries for
replica-tion, viral particle assembly and release. It is well
established thatmembrane trafficking machineries play key roles in
the viral lifecycle [146–148]. Most enveloped viruses enter cells
via clathrin-mediated endocytosis, and are trafficked through the
early endo-dome to the late endosome/lysosome, then release viral
materialsinto cytosol, via an unknown mechanism, due to
lysis/leakageof endosomal compartments. It has been revealed that
buddingand release of some viruses, such as HIV and HBV (hepatitis
Bvirus), requires MVB machineries, such as ESCRT
complexes[149–152].
Small GTPases participate in regulating viral life
cycle[153,154]. The effects of Rab7 on viral infection were
examinedfor some viruses (Table 3). Miyazawa et al. [155] reported
thatinternalized Ad7 (adenovirus serotype 7) was co-localized
withRab7 and other late endosomal/lysosomal markers, suggestingthat
the late endosomal trafficking pathway is involved in
viralinfection [155]. Sieczkarski and Whittaker [156] found
thatdominant-negative Rab7 inhibited infection of influenza
virus,without effects on the infection of SFV (Semliki Forest
virus) andVSV, which were inhibited by dominant-negative Rab5.
How-ever, the findings by Vonderheit and Helenius [157]
indicatedthat the internalized SFV is finally located to the Rab7
membrane
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Rab7 in membrane trafficking and disease
Figure 3 A common survival strategy for pathogens through
phagosome maturation arrest regulated by Rab7Non-pathogen
induced-vacuoles (nascent phagosome) can fuse with the early
endosome to form early phagosomesby acquisition of Rab5; early
phagosomes then fuse with late endosomes and lysosomes to form
phagosomes andphagolysosomes by acquisition of Rab7 and loss of
Rab5. Pathogen-induced vacuoles acquire Rab5 and fuse with theearly
endosomes to form early phagosomes; the pathogen-containing early
phagosome is prevented from fusion with lateendosomes and lysosomes
by pathogen-mediated exclusion of Rab7, allowing pathogen survival
in the arrested phago-some. Some pathogen-containing phagosomes are
also arrested by partial acquisition of late endosomal
components,including Rab7 (indicated by the broken line with an
arrow), and form late endosome–phagosome hybrids. See the text
forfurther details.
domain, excluding Rab5, Rab4, EEA1 and Arf1, and overexpress-ing
dominant-negative Rab7 resulted in accumulation of SFV inthe early
endosome [157]. Similarly, Kolokoltsov et al. [158]found that SFV
and VSV entry was reduced by 20% when Rab7-T22N was expressed in
cells. Quirin et al. [159] found SFV in-fection was not inhibited
by the corresponding Rab7-T22N con-struct, but an SFV mutant stain
(SFV fus-1) infection was in-hibited by Rab7-T22N. Feng et al. [21]
found that the VSV Gprotein was accumulated specifically in early
endosomes in babyhamster kidney cells expressing the Rab7-N125I
mutant. Vidri-caire and Tremblay [160] investigated the roles of
Rab7 in HIV-1infection in polarized human placental cells, and
demonstratedthat overexpression of both the dominant-negative and
dominant-active Rab7 resulted in an almost complete blockade of
HIV-1gene expression (up to 88% inhibition in viral expression was
ob-served). When studying the trafficking of HIV-1 genomic
RNA,Lévesque et al. [161] found that overexpression of RILP had
littleeffect on the synthesis of the polyprotein precursor Pr55Gag,
butnegatively influenced virus production and infectivity.
Recently,van der Schaar et al. [162] used live-cell imaging and
single-virustracking to investigate the cell entry, endocytic
trafficking and fu-sion behaviour of DENV (Dengue virus), and
demonstrated thatDENV matured in late endosomal compartments by
acquisitionof Rab7 and loss of Rab5, similar to the phagosome
maturation asdescribed above. On the other hand, Krishnan et al.
[163] found
that depletion of Rab7 or Rab7 mutant overexpression did
notimpair DENV and WNV (West Nile virus) infection of HeLacells. In
mammalian cells, data from Kolokoltsov et al. [158]demonstrated
that VEEV (Venezuelan equine encephalitis virus)entry was reduced
by Rab7-T22N by 80–90%. Similar findingsby Vela et al. [164]
revealed that Pichinde virus enters cellsthrough Rab5–early
endosomes, and then uncoats and fuses withRab7–late endosomes, and
knockdown of Rab7 resulted in 80%reduction of viral protein
production of Pichinde virus. Ding et al.[165] showed that
overexpression of Rab7 significantly decreasedrAAV2 (recombinant
adeno-associated virus type-2) transduc-tion. Meertens et al. [166]
found that expression of Rab7-T22Ninhibited entry of Ebola virus
pseudoparticles. Smith et al. [167]observed that HPV31 (human
papillomavirus type 31) capsids in-creased residence in the
caveosome in mutant-Rab7-transfectedcells, but no infection
inhibition was detected. The results suggestthat, although some
discrepancies exist between different studies,Rab7 and
Rab7-associated endosomes are intimately involved inentry of some
viruses.
Evidence for the involvement of Rab7 in viral infectionwere also
studied in a non-mammalian system. Suppression ofPmRab7 (a Rab7
homologue in Penaeus monodon) inhibitsthe infection of WSSV
(white-spot syndrome virus) throughinteraction with viral protein
VP28 [168], and similar inhibi-tion was also found for YHV
(yellow-head virus) in P. monodon
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M. Zhang and others
[169]. VEEV infection of mosquito cells requires the
mosquitohomologue of Rab7 [170]. The requirement for
Rab7-mediatedmembrane trafficking in viral infection of a
non-mammalian sys-tem revealed an evolutionarily conserved
pathway.
Rab7 may also be engaged in host-cell defence against
viruses;for example, the HIV-1 protein Nef targets MHC-I and CD4 to
aRab7-positive compartment for degradation [171], which may bethe
mechanism by which the virus escapes attack from the host’simmune
system. Taken together, Rab7-mediated endosomal traf-ficking plays
important roles in viral infection; however, the rolesof Rab7 in
the transport, assembly of newly synthesized viral pro-tein and
release of a new viral particle remain unclear. A recentfinding by
Shah et al. [172] characterized the group C adenov-irus protein
RIDα (receptor internalization and degradation α),which interacts
with RILP and ORP1L, both of which are effect-ors of Rab7. The
results of this study [172] also indicated thatRIDα mimics the
function of Rab7 to recruit RILP to endosomesto facilitate
down-regulation of the surface receptor. These dataprovide another
virus–host interaction model. Further studies
onRIDα–ORP1L–RILP–Rab7 orchestration may reveal
additionalmechanisms for Rab7 to regulate viral life cycle.
SUMMARY
In summary, Rab7 is engaged in divergent disease
pathogenesis,physiological disorders and infectious diseases. The
fundamentalmechanisms depend on the crucial role of Rab7 in
regulating en-docytic membrane trafficking, therefore governing the
biogenesisof endocytic compartments (late endosome, lysosome,
phago-some, autophagosome and other functionally similar
organelles)and linking the trafficking events to cell signalling
pathways thatinfluence multiple cellular events. Nevertheless, much
work re-mains to further the understanding of pathogenic
mechanismsfor regulation of diseases by Rab7, such as how the
function ofRab7 is regulated by its different effectors. The
significance ofthe interactions between Rab7 and its effectors in
regulating dis-ease pathogenesis has not been elucidated in detail.
Furthermore,since most investigations are carried out in vitro
using culturedcells, the in vivo system using animal models will
advance addi-tional knowledge about the underlying mechanisms of
Rab7 (orits partners) in endosomal trafficking and its involvement
in thedevelopment of various diseases.
FUNDING
This work was supported by the start-up funds for new
investigatorsfrom Xiamen University, People’s Republic of
China.
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