TBK1 is ubiquitinated by TRIM5α to assemble mitophagy machinery

Bhaskar Saha; Hallvard Olsvik; Geneva L. Williams; Seeun Oh; Gry Evjen; Eva Sjøttem; Michael A. Mandell

Cell Reports (Jun 2024)

TBK1 is ubiquitinated by TRIM5α to assemble mitophagy machinery

Bhaskar Saha,
Hallvard Olsvik,
Geneva L. Williams,
Seeun Oh,
Gry Evjen,
Eva Sjøttem,
Michael A. Mandell

Affiliations

Bhaskar Saha: Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Hallvard Olsvik: Autophagy Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
Geneva L. Williams: Biomedical Sciences Graduate Program, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Seeun Oh: Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Gry Evjen: Autophagy Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
Eva Sjøttem: Autophagy Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
Michael A. Mandell: Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Autophagy, Inflammation, and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Corresponding author

Journal volume & issue: Vol. 43, no. 6
p. 114294

Abstract

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Summary: Ubiquitination of mitochondrial proteins provides a basis for the downstream recruitment of mitophagy machinery, yet whether ubiquitination of the machinery itself contributes to mitophagy is unknown. Here, we show that K63-linked polyubiquitination of the key mitophagy regulator TBK1 is essential for its mitophagy functions. This modification is catalyzed by the ubiquitin ligase TRIM5α and is required for TBK1 to interact with and activate a set of ubiquitin-binding autophagy adaptors including NDP52, p62/SQSTM1, and NBR1. Autophagy adaptors, along with TRIM27, enable TRIM5α to engage with TBK1 following mitochondrial damage. TRIM5α’s ubiquitin ligase activity is required for the accumulation of active TBK1 on damaged mitochondria in Parkin-dependent and Parkin-independent mitophagy pathways. Our data support a model in which TRIM5α provides a mitochondria-localized, ubiquitin-based, self-amplifying assembly platform for TBK1 and mitophagy adaptors that is ultimately necessary for the recruitment of the core autophagy machinery.

CP: Cell biology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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