Unconventional Initiation of PINK1/Parkin Mitophagy by Optineurin
Creators
- 1. Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
- 2. Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna BioCenter, Dr. Bohr-Gasse 9, 1030 Vienna, Austria.
- 3. Center for Microscopy, Characterization and Analysis, University of Western Australia, Perth, 6009 Australia
- 4. Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna BioCenter, Dr. Bohr-Gasse 9, 1030 Vienna, Austria.a
Description
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.
Files
Figure 1.zip
Files
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Additional details
Funding
- Australian Research Council
- Discovery Projects - Grant ID: DP200100347 DP200100347
- Aligning Science Across Parkinson's
- Mechanisms of mitochondrial damage control by PINK1 and Parkin ASAP-000350
- National Health and Medical Research Council
- Defining the machinery for mitochondrial turnover governed by the Parkinson’s Disease proteins PINK1 and Parkin GNT1106471