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PMID: 29158324 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Control of RAB7 activity and localization through the retromer-TBC1D5 complex enables RAB7-dependent mitophagy.

The EMBO journal ·Vol. 37 ·No. 2 ·2018-00-17 ·Pages 235-254

Jimenez-Orgaz A, Kvainickas A, Nägele H, Denner J, Eimer S, Dengjel J, Steinberg F

Abstract

Retromer is an endosomal multi-protein complex that organizes the endocytic recycling of a vast range of integral membrane proteins. Here, we establish an additional retromer function in controlling the activity and localization of the late endosomal small GTPase RAB7. Surprisingly, we found that RAB7 not only decorates late endosomes or lysosomes, but is also present on the endoplasmic reticulum, trans-Golgi network, and mitochondrial membranes, a localization that is maintained by retromer and the retromer-associated RAB7-specific GAP TBC1D5. In the absence of either TBC1D5 or retromer, RAB7 activity state and localization are no longer controlled and hyperactivated RAB7 expands over the entire lysosomal domain. This lysosomal accumulation of hyperactivated RAB7 results in a striking loss of RAB7 mobility and overall depletion of the inactive RAB7 pool on endomembranes. Functionally, we establish that this control of RAB7 activity is not required for the recycling of retromer-dependent cargoes, but instead enables the correct sorting of the autophagy related transmembrane protein ATG9a and autophagosome formation around damaged mitochondria during Parkin-mediated mitophagy.

Keywords
RAB7 TBC1D5 membrane trafficking mitophagy retromer
MeSH Terms
Autophagosomes/metabolism Autophagy-Related Proteins/metabolism GTPase-Activating Proteins/genetics,metabolism HeLa Cells Humans Lysosomes/genetics,metabolism Membrane Proteins/metabolism Mitochondria/genetics,metabolism Mitophagy/physiology Ubiquitin-Protein Ligases/genetics,metabolism Vesicular Transport Proteins/metabolism rab GTP-Binding Proteins/genetics,metabolism rab7 GTP-Binding Proteins
Chemicals
Atg9a protein, human Autophagy-Related Proteins GTPase-Activating Proteins Membrane Proteins TBC1D5 protein, human Vesicular Transport Proteins rab7 GTP-Binding Proteins rab7 GTP-binding proteins, human Ubiquitin-Protein Ligases parkin protein rab GTP-Binding Proteins
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Jimenez-Orgaz Ana
Center for Biological Systems Analysis (ZBSA), Faculty of Biology, Albert Ludwigs Universitaet Freiburg, Freiburg, Germany.
Kvainickas Arunas
Center for Biological Systems Analysis (ZBSA), Faculty of Biology, Albert Ludwigs Universitaet Freiburg, Freiburg, Germany.
Nägele Heike
Center for Biological Systems Analysis (ZBSA), Faculty of Biology, Albert Ludwigs Universitaet Freiburg, Freiburg, Germany.
Denner Justin
Center for Biological Systems Analysis (ZBSA), Faculty of Biology, Albert Ludwigs Universitaet Freiburg, Freiburg, Germany.
Eimer Stefan
Center for Biological Systems Analysis (ZBSA), Faculty of Biology, Albert Ludwigs Universitaet Freiburg, Freiburg, Germany.
Dengjel Jörn ORCID
Department of Biology, Fribourg University, Fribourg, Switzerland.
Steinberg Florian ORCID
Center for Biological Systems Analysis (ZBSA), Faculty of Biology, Albert Ludwigs Universitaet Freiburg, Freiburg, Germany florian.steinberg@zbsa.de.
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.15252/embj.201797128
Email
florian.steinberg@zbsa.de
Published
2018-00-17
Epub
2017-00-20
Pages
235-254
Language
English
Region
England
NLM ID
8208664
PMCID
PMC5770787
Subset
IM
External Links
PubMed source DOI: 10.15252/embj.201797128 PMC Full Text View journal details
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