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Unconventional Initiation of PINK1/Parkin Mitophagy by Optineurin

View ORCID ProfileThanh Ngoc Nguyen, View ORCID ProfileJustyna Sawa-Makarska, Grace Khuu, View ORCID ProfileWai Kit Lam, Elias Adriaenssens, View ORCID ProfileDorotea Fracchiolla, Stephen Shoebridge, View ORCID ProfileBenjamin Scott Padman, View ORCID ProfileMarvin Skulsuppaisarn, View ORCID ProfileRuna S.J. Lindblom, View ORCID ProfileSascha Martens, View ORCID ProfileMichael Lazarou
doi: https://doi.org/10.1101/2022.08.14.503930
Thanh Ngoc Nguyen
1Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
2Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
3Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia
4Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD 20185, USA
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  • For correspondence: Lazarou.m@wehi.edu.au sascha.martens@univie.ac.at nguyen.tha@wehi.edu.au
Justyna Sawa-Makarska
4Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD 20185, USA
5Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna BioCenter, Dr. Bohr-Gasse 9, 1030 Vienna, Austria
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Grace Khuu
1Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
2Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
3Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia
4Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD 20185, USA
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Wai Kit Lam
1Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
2Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
3Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia
4Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD 20185, USA
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Elias Adriaenssens
4Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD 20185, USA
5Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna BioCenter, Dr. Bohr-Gasse 9, 1030 Vienna, Austria
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Dorotea Fracchiolla
4Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD 20185, USA
5Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna BioCenter, Dr. Bohr-Gasse 9, 1030 Vienna, Austria
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Stephen Shoebridge
4Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD 20185, USA
5Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna BioCenter, Dr. Bohr-Gasse 9, 1030 Vienna, Austria
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Benjamin Scott Padman
3Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia
4Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD 20185, USA
6Center for Microscopy, Characterization and Analysis, University of Western Australia, Perth, 6009 Australia
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Marvin Skulsuppaisarn
1Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
2Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
3Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia
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Runa S.J. Lindblom
1Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
2Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
3Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia
4Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD 20185, USA
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Sascha Martens
4Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD 20185, USA
5Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna BioCenter, Dr. Bohr-Gasse 9, 1030 Vienna, Austria
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  • For correspondence: Lazarou.m@wehi.edu.au sascha.martens@univie.ac.at nguyen.tha@wehi.edu.au
Michael Lazarou
1Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
2Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
3Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia
4Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD 20185, USA
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  • For correspondence: Lazarou.m@wehi.edu.au sascha.martens@univie.ac.at nguyen.tha@wehi.edu.au
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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 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.

Competing Interest Statement

Sascha Martens is member of the scientific advisory board of Casma Therapeutics. Michael Lazarou is a member of the scientific advisory board of Automera and a consultant for Casma Therapeutics.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted August 15, 2022.
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Unconventional Initiation of PINK1/Parkin Mitophagy by Optineurin
Thanh Ngoc Nguyen, Justyna Sawa-Makarska, Grace Khuu, Wai Kit Lam, Elias Adriaenssens, Dorotea Fracchiolla, Stephen Shoebridge, Benjamin Scott Padman, Marvin Skulsuppaisarn, Runa S.J. Lindblom, Sascha Martens, Michael Lazarou
bioRxiv 2022.08.14.503930; doi: https://doi.org/10.1101/2022.08.14.503930
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Unconventional Initiation of PINK1/Parkin Mitophagy by Optineurin
Thanh Ngoc Nguyen, Justyna Sawa-Makarska, Grace Khuu, Wai Kit Lam, Elias Adriaenssens, Dorotea Fracchiolla, Stephen Shoebridge, Benjamin Scott Padman, Marvin Skulsuppaisarn, Runa S.J. Lindblom, Sascha Martens, Michael Lazarou
bioRxiv 2022.08.14.503930; doi: https://doi.org/10.1101/2022.08.14.503930

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