Unconventional initiation of PINK1/Parkin mitophagy by Optineurin
- Author(s)
- Nguyen, TN; Sawa-Makarska, J; Khuu, G; Lam, WK; Adriaenssens, E; Fracchiolla, D; Shoebridge, S; Bernklau, D; Padman, BS; Skulsuppaisarn, M; Lindblom, RSJ; Martens, S; Lazarou, M;
- Details
- Publication Year 2023-05-18,Volume 83,Issue #10,Page 1693-1709.e9
- Journal Title
- Molecular Cell
- Abstract
- Cargo sequestration is a fundamental step of selective autophagy in which cells generate a double-membrane structure termed an "autophagosome" on the surface of cargoes. NDP52, TAX1BP1, and p62 bind FIP200, which recruits the ULK1/2 complex to initiate autophagosome formation on cargoes. How OPTN initiates autophagosome formation during selective autophagy remains unknown despite its importance in neurodegeneration. Here, we uncover an unconventional path of PINK1/Parkin mitophagy initiation by OPTN that does not begin with FIP200 binding or require the ULK1/2 kinases. Using gene-edited cell lines and in vitro reconstitutions, we show that OPTN utilizes the kinase TBK1, which binds directly to the class III phosphatidylinositol 3-kinase complex I to initiate mitophagy. During NDP52 mitophagy initiation, TBK1 is functionally redundant with ULK1/2, classifying TBK1's role as a selective autophagy-initiating kinase. Overall, this work reveals that OPTN mitophagy initiation is mechanistically distinct and highlights the mechanistic plasticity of selective autophagy pathways.
- Publisher
- Cell Press
- Keywords
- Mitophagy; Ubiquitin-Protein Ligases/genetics/metabolism; Autophagosomes/metabolism; Apoptosis Regulatory Proteins; Protein Kinases/genetics/metabolism; Autophagy; Optn; Pink1; Parkin; Tbk1; autophagosome; selective autophagy
- Research Division(s)
- Ubiquitin Signalling
- PubMed ID
- 37207627
- Publisher's Version
- https://doi.org/10.1016/j.molcel.2023.04.021
- Open Access at Publisher's Site
https://doi.org/10.1016/j.molcel.2023.04.021- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-06-07 03:10:39
Last Modified: 2023-06-07 03:37:16