Cdc48 regulates a deubiquitylase cascade critical for mitochondrial fusion

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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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Tânia Simões

Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

Competing interests
The authors declare that no competing interests exist.
Ramona Schuster

Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

Competing interests
The authors declare that no competing interests exist.
Fabian den Brave

Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany

Competing interests
The authors declare that no competing interests exist.
Mafalda Escobar-Henriques

Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

For correspondence
mafalda.escobar@uni-koeln.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0879-3119

Funding

Deutsche Forschungsgemeinschaft (ES338/3-1)

Mafalda Escobar-Henriques

Universität zu Köln (German Excellence Initiative and Faculty of Mathematics and Natural Sciences)

Mafalda Escobar-Henriques

Deutsche Forschungsgemeinschaft (SFB635)

Mafalda Escobar-Henriques

Deutsche Forschungsgemeinschaft (CRC1218TPA03)

Mafalda Escobar-Henriques

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.