Cargando…

GSK3B-mediated phosphorylation of MCL1 regulates axonal autophagy to promote Wallerian degeneration

Macroautophagy is a catabolic process, in which portions of cytoplasm or organelles are delivered to lysosomes for degradation. Emerging evidence has indicated a pathological connection between axonal degeneration and autophagy. However, the physiological function and induction mechanism of autophag...

Descripción completa

Detalles Bibliográficos
Autores principales: Wakatsuki, Shuji, Tokunaga, Shinji, Shibata, Megumi, Araki, Toshiyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294778/
https://www.ncbi.nlm.nih.gov/pubmed/28053206
http://dx.doi.org/10.1083/jcb.201606020
_version_ 1782505302927605760
author Wakatsuki, Shuji
Tokunaga, Shinji
Shibata, Megumi
Araki, Toshiyuki
author_facet Wakatsuki, Shuji
Tokunaga, Shinji
Shibata, Megumi
Araki, Toshiyuki
author_sort Wakatsuki, Shuji
collection PubMed
description Macroautophagy is a catabolic process, in which portions of cytoplasm or organelles are delivered to lysosomes for degradation. Emerging evidence has indicated a pathological connection between axonal degeneration and autophagy. However, the physiological function and induction mechanism of autophagy in axons remain elusive. We herein show that, through activation of BECLIN1, glycogen synthase kinase 3B (GSK3B)–mediated phosphorylation of BCL2 family member MCL1 induces axonal autophagy and axonal degeneration. Phosphorylated MCL1 is ubiquitinated by the FBXW7 ubiquitin ligase and degraded by the proteasome, thereby releasing BECLIN1 to induce axonal autophagy. Axonal autophagy contributes to local adenosine triphosphate production in degenerating axons and the exposure of phosphatidylserine—an “eat-me” signal for phagocytes—on transected axons and is required for normal recruitment of phagocytes to axonal debris in vivo. These results suggest that GSK3B–MCL1 signaling to regulate autophagy might be important for the successful completion of Wallerian degeneration.
format Online
Article
Text
id pubmed-5294778
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-52947782017-08-01 GSK3B-mediated phosphorylation of MCL1 regulates axonal autophagy to promote Wallerian degeneration Wakatsuki, Shuji Tokunaga, Shinji Shibata, Megumi Araki, Toshiyuki J Cell Biol Research Articles Macroautophagy is a catabolic process, in which portions of cytoplasm or organelles are delivered to lysosomes for degradation. Emerging evidence has indicated a pathological connection between axonal degeneration and autophagy. However, the physiological function and induction mechanism of autophagy in axons remain elusive. We herein show that, through activation of BECLIN1, glycogen synthase kinase 3B (GSK3B)–mediated phosphorylation of BCL2 family member MCL1 induces axonal autophagy and axonal degeneration. Phosphorylated MCL1 is ubiquitinated by the FBXW7 ubiquitin ligase and degraded by the proteasome, thereby releasing BECLIN1 to induce axonal autophagy. Axonal autophagy contributes to local adenosine triphosphate production in degenerating axons and the exposure of phosphatidylserine—an “eat-me” signal for phagocytes—on transected axons and is required for normal recruitment of phagocytes to axonal debris in vivo. These results suggest that GSK3B–MCL1 signaling to regulate autophagy might be important for the successful completion of Wallerian degeneration. The Rockefeller University Press 2017-02 /pmc/articles/PMC5294778/ /pubmed/28053206 http://dx.doi.org/10.1083/jcb.201606020 Text en © 2017 Wakatsuki et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Wakatsuki, Shuji
Tokunaga, Shinji
Shibata, Megumi
Araki, Toshiyuki
GSK3B-mediated phosphorylation of MCL1 regulates axonal autophagy to promote Wallerian degeneration
title GSK3B-mediated phosphorylation of MCL1 regulates axonal autophagy to promote Wallerian degeneration
title_full GSK3B-mediated phosphorylation of MCL1 regulates axonal autophagy to promote Wallerian degeneration
title_fullStr GSK3B-mediated phosphorylation of MCL1 regulates axonal autophagy to promote Wallerian degeneration
title_full_unstemmed GSK3B-mediated phosphorylation of MCL1 regulates axonal autophagy to promote Wallerian degeneration
title_short GSK3B-mediated phosphorylation of MCL1 regulates axonal autophagy to promote Wallerian degeneration
title_sort gsk3b-mediated phosphorylation of mcl1 regulates axonal autophagy to promote wallerian degeneration
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294778/
https://www.ncbi.nlm.nih.gov/pubmed/28053206
http://dx.doi.org/10.1083/jcb.201606020
work_keys_str_mv AT wakatsukishuji gsk3bmediatedphosphorylationofmcl1regulatesaxonalautophagytopromotewalleriandegeneration
AT tokunagashinji gsk3bmediatedphosphorylationofmcl1regulatesaxonalautophagytopromotewalleriandegeneration
AT shibatamegumi gsk3bmediatedphosphorylationofmcl1regulatesaxonalautophagytopromotewalleriandegeneration
AT arakitoshiyuki gsk3bmediatedphosphorylationofmcl1regulatesaxonalautophagytopromotewalleriandegeneration