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

doi:10.1101/2023.10.19.563195

TBK1 is ubiquitinated by TRIM5α to assemble mitophagy machinery

bioRxiv [Preprint]. 2023 Oct 20:2023.10.19.563195. doi: 10.1101/2023.10.19.563195.

Authors

Bhaskar Saha¹, Hallvard Olsvik², Geneva L Williams³, Seeun Oh¹, Gry Evjen², Eva Sjøttem², Michael A Mandell^{1

4}

Affiliations

¹ Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 USA.
² Autophagy Research Group, Department of Medical Biology, University of Tromsø-The Arctic University of Norway, Tromsø, Norway.
³ Biomedical Sciences Graduate Program, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 USA.
⁴ Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center.

Abstract

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. Mitochondrial damage triggers TRIM5α's auto-ubiquitination and its interaction with ubiquitin-binding autophagy adaptors including NDP52, optineurin, and NBR1. Autophagy adaptors, along with TRIM27, enable TRIM5α to engage with TBK1. TRIM5α with intact ubiquitination function is required for the proper accumulation of active TBK1 on damaged mitochondria in Parkin-dependent and Parkin-independent mitophagy pathways. Additionally, we show that TRIM5α can directly recruit autophagy initiation machinery to damaged mitochondria. Our data support a model in which TRIM5α provides a self-amplifying, mitochondria-localized, ubiquitin-based, assembly platform for TBK1 and mitophagy adaptors that is ultimately required to recruit the core autophagy machinery.

Keywords: LC3 interacting (LIR) motif; NBR1; NDP52; Optineurin; TAX1BP1; TBK1; TRIM27/RFP; TRIM5α; Tripartite-motif; autophagy; p62; ubiquitin ligase.

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Preprint

Abstract

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