Cdc48 regulates a deubiquitylase cascade critical for mitochondrial fusion

ELife
Tânia SimõesMafalda Escobar-Henriques

Abstract

Cdc48/p97, a ubiquitin-selective chaperone, orchestrates the function of E3 ligases and deubiquitylases (DUBs). Here, we identify a new function of Cdc48 in ubiquitin-dependent regulation of mitochondrial dynamics. The DUBs Ubp12 and Ubp2 exert opposing effects on mitochondrial fusion and cleave different ubiquitin chains on the mitofusin Fzo1. We demonstrate that Cdc48 integrates the activities of these two DUBs, which are themselves ubiquitylated. First, Cdc48 promotes proteolysis of Ubp12, stabilizing pro-fusion ubiquitylation on Fzo1. Second, loss of Ubp12 stabilizes Ubp2 and thereby facilitates removal of ubiquitin chains on Fzo1 inhibiting fusion. Thus, Cdc48 synergistically regulates the ubiquitylation status of Fzo1, allowing to control the balance between activation or repression of mitochondrial fusion. In conclusion, we unravel a new cascade of ubiquitylation events, comprising Cdc48 and two DUBs, fine-tuning the fusogenic activity of Fzo1.

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Citations

May 29, 2018·ELife·Tom CornelissenWim Vandenberghe
May 30, 2019·Molecular Biology of the Cell·Jenna M GoodrumAdam L Hughes
Jun 4, 2019·Frontiers in Physiology·Mafalda Escobar-Henriques, Mariana Joaquim
Sep 24, 2020·International Journal of Molecular Sciences·Mafalda Escobar-Henriques, Vincent Anton
Jun 21, 2018·Journal of Biochemistry·Abhijit ChowdhuryMasatoshi Esaki
May 12, 2020·Frontiers in Cell and Developmental Biology·Sonia RavanelliThorsten Hoppe
Dec 21, 2019·Life Science Alliance·Ramona SchusterMafalda Escobar-Henriques
Nov 30, 2020·FEBS Letters·Lena KrämerJohannes M Herrmann
Oct 24, 2020·Nature Reviews. Molecular Cell Biology·Jiyao SongThomas Becker
Aug 31, 2020·Biochimica Et Biophysica Acta. Bioenergetics·Cynthia AlsayyahMickael M Cohen

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Methods Mentioned

BETA
GTPases
fluorescence microscopy
immunoprecipitation
co-immunoprecipitation

Software Mentioned

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