Unconventional initiation of PINK1/Parkin mitophagy by Optineurin.

• DOI: 10.5281/zenodo.7902562
• Publication Date: 2023-05-01
• Authors: Nguyen, Thanh Ngoc; Sawa-Makarska, Ju...; Khuu, Grace; Lam, Wai Kit; Adriaenssens, Elias; Fracchiolla, Dorotea; Shoebridge, Stephen; Bernklau, Daniel; Padman, Benjamin ...; Skulsuppaisarn, M...; Lindblom, Runa S.J.; Martens, Sascha; Lazarou, Michael
• Keywords: selective autophagy; autophagy; TBK1; PINK1; Ubiquitin-Protein Ligases; 106002 Biochemie; autophagosome; Mitophagy; Autophagosomes; 106002 Biochemistry; OPTN; Autophagy; Apoptosis Regulatory Proteins; Protein Kinases; Parkin

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 nor 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.