Starvation-induced MTMR13 and RAB21 activity regulates VAMP8 to promote autophagosome-lysosome fusion

Autophagy, the process for recycling cytoplasm in the lysosome, depends on membrane trafficking. We previously identified Drosophila Sbf as a Rab21 guanine nucleotide exchange factor (GEF) that acts with Rab21 in endosomal trafficking. Here, we show that Sbf/MTMR13 and Rab21 have conserved functions...

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Bibliographic Details
Published in:EMBO reports 2015-03, Vol.16 (3), p.297-311
Main Authors: Jean, Steve, Cox, Sarah, Nassari, Sonya, Kiger, Amy A
Format: Article
Language:English
Subjects:
Animals
Autophagy
Autophagy - physiology
Crosses, Genetic
Drosophila
Electrophoresis, Polyacrylamide Gel
HeLa Cells
Humans
Immunoblotting
Immunoprecipitation
Insects
Lysosomes - metabolism
Microscopy, Electron, Transmission
Microscopy, Fluorescence
MTMR13
Phagosomes - metabolism
Protein Tyrosine Phosphatases, Non-Receptor - metabolism
R-SNARE Proteins - metabolism
rab GTP-Binding Proteins - metabolism
Rab21
RNA, Small Interfering - genetics
Sbf
Scientific Reports
Starvation - metabolism
Statistics, Nonparametric
VAMP8
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Summary:Autophagy, the process for recycling cytoplasm in the lysosome, depends on membrane trafficking. We previously identified Drosophila Sbf as a Rab21 guanine nucleotide exchange factor (GEF) that acts with Rab21 in endosomal trafficking. Here, we show that Sbf/MTMR13 and Rab21 have conserved functions required for starvation‐induced autophagy. Depletion of Sbf/MTMR13 or Rab21 blocked endolysosomal trafficking of VAMP8, a SNARE required for autophagosome–lysosome fusion. We show that starvation induces Sbf/MTMR13 GEF and RAB21 activity, as well as their induced binding to VAMP8 (or closest Drosophila homolog, Vamp7). MTMR13 is required for RAB21 activation, VAMP8 interaction and VAMP8 endolysosomal trafficking, defining a novel GEF‐Rab‐effector pathway. These results identify starvation‐responsive endosomal regulators and trafficking that tunes membrane demands with changing autophagy status. Synopsis Sbf/MTMR13 and Rab21 promote endosomal sorting of VAMP8 required for autophagosome–lysosome fusion. Starvation induces Sbf/MTMR13 GEF and Rab21 activity, the binding to VAMP8 and VAMP8 trafficking to endolysosomes where it mediates autophagosome fusion. Endosomal Sbf/MTMR13 and RAB21 functions are needed for autophagosome–lysosome fusion in flies and humans. Starvation induces MTMR13 GEF and RAB21 activity, leading to an increase in VAMP8 interaction, VAMP8 endolysosomal trafficking and SNARE endolysosomal redistribution. Sbf/MTMR13 and Rab21 promote endosomal sorting of VAMP8 required for autophagosome–lysosome fusion. Starvation induces Sbf/MTMR13 GEF and Rab21 activity, the binding to VAMP8 and VAMP8 trafficking to endolysosomes where it mediates autophagosome fusion.
ISSN:1469-221X
1469-3178
DOI:10.15252/embr.201439464