Cargando…

Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5–dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics

MARCH5, an OMM-associated E3 ubiquitin ligase, controls mitochondrial function. Despite its importance, the mechanism and factors controlling MARCH5 activity are largely unknown. Here we report that the MARCH5 C-terminal domain plays a critical role in degradation of MARCH5 substrates, likely by fac...

Descripción completa

Detalles Bibliográficos
Autores principales: Cherok, Edward, Xu, Shan, Li, Sunan, Das, Shweta, Meltzer, W. Alex, Zalzman, Michal, Wang, Chunxin, Karbowski, Mariusz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341724/
https://www.ncbi.nlm.nih.gov/pubmed/27932492
http://dx.doi.org/10.1091/mbc.E16-04-0208
_version_ 1782513027428384768
author Cherok, Edward
Xu, Shan
Li, Sunan
Das, Shweta
Meltzer, W. Alex
Zalzman, Michal
Wang, Chunxin
Karbowski, Mariusz
author_facet Cherok, Edward
Xu, Shan
Li, Sunan
Das, Shweta
Meltzer, W. Alex
Zalzman, Michal
Wang, Chunxin
Karbowski, Mariusz
author_sort Cherok, Edward
collection PubMed
description MARCH5, an OMM-associated E3 ubiquitin ligase, controls mitochondrial function. Despite its importance, the mechanism and factors controlling MARCH5 activity are largely unknown. Here we report that the MARCH5 C-terminal domain plays a critical role in degradation of MARCH5 substrates, likely by facilitating release of ubiquitinated proteins from the OMM. We also found that the mitochondrial fission proteins Drp1 and Mff negatively regulate MARCH5’s activity toward MiD49 and Mcl1. Knockouts of either Drp1 or Mff led to reduced expression, shorter half-lives, and increased ubiquitination of MiD49 and Mcl1. Effects of Mff and Drp1 depletion on degradation rates and ubiquitination of Mcl1 and MiD49 were eliminated in Drp1(−/−)/MARCH5(−/−) and Mff(−/−)/MARCH5(−/−) cells. Our data show that it is not mitochondrial morphology per se but rather Mff and Drp1 that directly control MARCH5. Consistently, we find that Mff is an integral component of the MARCH5/p97/Npl4 complex, which is also controlled by MARCH5’s C-terminal domain. Furthermore, not only mitochondrial fission but also fusion is regulated through Mff and Drp1 protein activities. Thus, in addition to their canonical roles in mitochondrial fission, Mff and Drp1 also act as regulatory factors that control mitochondrial fission and fusion.
format Online
Article
Text
id pubmed-5341724
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher The American Society for Cell Biology
record_format MEDLINE/PubMed
spelling pubmed-53417242017-04-16 Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5–dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics Cherok, Edward Xu, Shan Li, Sunan Das, Shweta Meltzer, W. Alex Zalzman, Michal Wang, Chunxin Karbowski, Mariusz Mol Biol Cell Articles MARCH5, an OMM-associated E3 ubiquitin ligase, controls mitochondrial function. Despite its importance, the mechanism and factors controlling MARCH5 activity are largely unknown. Here we report that the MARCH5 C-terminal domain plays a critical role in degradation of MARCH5 substrates, likely by facilitating release of ubiquitinated proteins from the OMM. We also found that the mitochondrial fission proteins Drp1 and Mff negatively regulate MARCH5’s activity toward MiD49 and Mcl1. Knockouts of either Drp1 or Mff led to reduced expression, shorter half-lives, and increased ubiquitination of MiD49 and Mcl1. Effects of Mff and Drp1 depletion on degradation rates and ubiquitination of Mcl1 and MiD49 were eliminated in Drp1(−/−)/MARCH5(−/−) and Mff(−/−)/MARCH5(−/−) cells. Our data show that it is not mitochondrial morphology per se but rather Mff and Drp1 that directly control MARCH5. Consistently, we find that Mff is an integral component of the MARCH5/p97/Npl4 complex, which is also controlled by MARCH5’s C-terminal domain. Furthermore, not only mitochondrial fission but also fusion is regulated through Mff and Drp1 protein activities. Thus, in addition to their canonical roles in mitochondrial fission, Mff and Drp1 also act as regulatory factors that control mitochondrial fission and fusion. The American Society for Cell Biology 2017-02-01 /pmc/articles/PMC5341724/ /pubmed/27932492 http://dx.doi.org/10.1091/mbc.E16-04-0208 Text en © 2017 Cherok et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Cherok, Edward
Xu, Shan
Li, Sunan
Das, Shweta
Meltzer, W. Alex
Zalzman, Michal
Wang, Chunxin
Karbowski, Mariusz
Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5–dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics
title Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5–dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics
title_full Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5–dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics
title_fullStr Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5–dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics
title_full_unstemmed Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5–dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics
title_short Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5–dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics
title_sort novel regulatory roles of mff and drp1 in e3 ubiquitin ligase march5–dependent degradation of mid49 and mcl1 and control of mitochondrial dynamics
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341724/
https://www.ncbi.nlm.nih.gov/pubmed/27932492
http://dx.doi.org/10.1091/mbc.E16-04-0208
work_keys_str_mv AT cherokedward novelregulatoryrolesofmffanddrp1ine3ubiquitinligasemarch5dependentdegradationofmid49andmcl1andcontrolofmitochondrialdynamics
AT xushan novelregulatoryrolesofmffanddrp1ine3ubiquitinligasemarch5dependentdegradationofmid49andmcl1andcontrolofmitochondrialdynamics
AT lisunan novelregulatoryrolesofmffanddrp1ine3ubiquitinligasemarch5dependentdegradationofmid49andmcl1andcontrolofmitochondrialdynamics
AT dasshweta novelregulatoryrolesofmffanddrp1ine3ubiquitinligasemarch5dependentdegradationofmid49andmcl1andcontrolofmitochondrialdynamics
AT meltzerwalex novelregulatoryrolesofmffanddrp1ine3ubiquitinligasemarch5dependentdegradationofmid49andmcl1andcontrolofmitochondrialdynamics
AT zalzmanmichal novelregulatoryrolesofmffanddrp1ine3ubiquitinligasemarch5dependentdegradationofmid49andmcl1andcontrolofmitochondrialdynamics
AT wangchunxin novelregulatoryrolesofmffanddrp1ine3ubiquitinligasemarch5dependentdegradationofmid49andmcl1andcontrolofmitochondrialdynamics
AT karbowskimariusz novelregulatoryrolesofmffanddrp1ine3ubiquitinligasemarch5dependentdegradationofmid49andmcl1andcontrolofmitochondrialdynamics