Maturation of autophagosomes and endosomes: A key role for Rab7

Hyttinen, Juha M. T.; Niittykoski, Minna; Salminen, Antero; Kaarniranta, Kai

doi:10.1016/j.bbamcr.2012.11.018

Cited by 333 publications

(307 citation statements)

References 91 publications

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“…Using VACV as ligand, we found that the process of macropinosome maturation shares many features with the maturation of endosomes 3, phagosomes 74 and autophagosomes 75. Our findings indicated that maturation was essential for the infectivity of VACV MVs and EVs (Figure 6).…”

Section: Discussionmentioning

confidence: 74%

Vaccinia Virus Infection Requires Maturation of Macropinosomes

Rizopoulos

Balistreri

Kilcher

et al. 2015

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The prototypic poxvirus, vaccinia virus (VACV), occurs in two infectious forms, mature virions (MVs) and extracellular virions (EVs). Both enter HeLa cells by inducing macropinocytic uptake. Using confocal microscopy, live‐cell imaging, targeted RNAi screening and perturbants of endosome maturation, we analyzed the properties and maturation pathway of the macropinocytic vacuoles containing VACV MVs in HeLa cells. The vacuoles first acquired markers of early endosomes [Rab5, early endosome antigen 1 and phosphatidylinositol(3)P]. Prior to release of virus cores into the cytoplasm, they contained markers of late endosomes and lysosomes (Rab7a, lysosome‐associated membrane protein 1 and sorting nexin 3). RNAi screening of endocytic cell factors emphasized the importance of late compartments for VACV infection. Follow‐up perturbation analysis showed that infection required Rab7a and PIKfyve, confirming that VACV is a late‐penetrating virus dependent on macropinosome maturation. VACV EV infection was inhibited by depletion of many of the same factors, indicating that both infectious particle forms share the need for late vacuolar conditions for penetration.

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Section: Discussionmentioning

confidence: 74%

Vaccinia Virus Infection Requires Maturation of Macropinosomes

Rizopoulos

Balistreri

Kilcher

et al. 2015

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“…12 , 41 , 42 However, to verify that indeed CMT2B mutations in this gene do not affect also early phases of autophagosomal biogenesis, we evaluated the expression of the ATG12–ATG5 complex upon prolonged serum starvation. 38 , 39 , 43 Interestingly, ATG12–ATG5 levels similarly increased in normal and CMT2B fibroblasts, indicating that autophagosomal biogenesis was not affected by the RAB7 V162M mutation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…10–12 To investigate the role of RAB7 in the endocytic pathway, previous studies have used the dominant negative RAB7 T22N mutant, which displays reduced affinity for GTP and impaired nucleotide exchange, thus being mainly GDP-bound, and the constitutively active RAB7 Q67L mutant, which displays impaired intrinsic GTP hydrolysis, thus being mainly GTP-bound. 13 …”

Section: Introductionmentioning

confidence: 99%

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Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B

et al. 2018

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Charcot-Marie-Tooth type 2B (CMT2B) disease is a dominant axonal peripheral neuropathy caused by 5 mutations in the RAB7A gene, a ubiquitously expressed GTPase controlling late endocytic trafficking. In neurons, RAB7A also controls neuronal-specific processes such as NTF (neurotrophin) trafficking and signaling, neurite outgrowth and neuronal migration. Given the involvement of macroautophagy/autophagy in several neurodegenerative diseases and considering that RAB7A is fundamental for autophagosome maturation, we investigated whether CMT2B-causing mutants affect the ability of this gene to regulate autophagy. In HeLa cells, we observed a reduced localization of all CMT2B-causing RAB7A mutants on autophagic compartments. Furthermore, compared to expression of RAB7AWT, expression of these mutants caused a reduced autophagic flux, similar to what happens in cells expressing the dominant negative RAB7AT22N mutant. Consistently, both basal and starvation-induced autophagy were strongly inhibited in skin fibroblasts from a CMT2B patient carrying the RAB7AV162M mutation, suggesting that alteration of the autophagic flux could be responsible for neurodegeneration.

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“…[15][16][17] We refer the reader to a number of excellent reviews that provide an extensive overview of Rab7 function in membrane trafficking. 15,16,18,19 More recently, attention has focused on the role of an Arl GTPase, Arl8-the only known small GTP-binding protein that is present primarily on mature lysosomes. 20 Arl8 is emerging as an important regulator of lysosome motility and membrane trafficking in several organisms.…”

Section: Introductionmentioning

confidence: 99%