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GAK and PRKCD are positive regulators of PRKN-independent mitophagy

View ORCID ProfileMichael J. Munson, Benan J. Mathai, Laura Trachsel, Matthew Yoke Wui Ng, Laura Rodriguez de la Ballina, Sebastian W. Schultz, Yahyah Aman, Alf H. Lystad, Sakshi Singh, Sachin Singh, Jørgen Wesche, View ORCID ProfileEvandro F. Fang, View ORCID ProfileAnne Simonsen
doi: https://doi.org/10.1101/2020.11.05.369496
Michael J. Munson
1Division of Biochemistry, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo
2Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0316, Oslo, Norway
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  • ORCID record for Michael J. Munson
  • For correspondence: michael.munson@astrazeneca.com anne.simonsen@medisin.uio.no
Benan J. Mathai
1Division of Biochemistry, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo
2Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0316, Oslo, Norway
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Laura Trachsel
1Division of Biochemistry, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo
2Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0316, Oslo, Norway
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Matthew Yoke Wui Ng
1Division of Biochemistry, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo
2Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0316, Oslo, Norway
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Laura Rodriguez de la Ballina
1Division of Biochemistry, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo
2Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0316, Oslo, Norway
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Sebastian W. Schultz
2Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0316, Oslo, Norway
3Department of Molecular Cell Biology, The Norwegian Radium Hospital Montebello, N-0379, Oslo, Norway
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Yahyah Aman
4Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway
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Alf H. Lystad
1Division of Biochemistry, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo
2Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0316, Oslo, Norway
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Sakshi Singh
1Division of Biochemistry, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo
2Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0316, Oslo, Norway
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Sachin Singh
2Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0316, Oslo, Norway
3Department of Molecular Cell Biology, The Norwegian Radium Hospital Montebello, N-0379, Oslo, Norway
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Jørgen Wesche
2Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0316, Oslo, Norway
3Department of Molecular Cell Biology, The Norwegian Radium Hospital Montebello, N-0379, Oslo, Norway
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Evandro F. Fang
4Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway
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Anne Simonsen
1Division of Biochemistry, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo
2Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0316, Oslo, Norway
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  • For correspondence: michael.munson@astrazeneca.com anne.simonsen@medisin.uio.no
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ABSTRACT

The mechanisms involved in programmed or damage-induced removal of mitochondria by mitophagy in response to different stimuli remains elusive. Here, we have screened for regulators of PRKN-independent mitophagy using an siRNA library targeting 197 proteins containing lipid interacting domains. We identify Cyclin G-associated kinase (GAK) and Protein Kinase C Delta (PRKCD) as novel regulators of PRKN-independent mitophagy, with both being dispensable for PRKN-dependent mitophagy and starvation-induced autophagy. We demonstrate that the kinase activity of both GAK and PRKCD are required for efficient mitophagy in vitro, that PRKCD is present on mitochondria, and that PRKCD is required for ULK1/ATG13 recruitment to early autophagic structures. Importantly, we demonstrate in vivo relevance for both kinases in the regulation of basal mitophagy. Knockdown of GAK homologue (gakh-1) in C.elegans or PRKCD homologues in zebrafish led to significant inhibition of basal mitophagy, highlighting the evolutionary relevance of these kinases in mitophagy.

Competing Interest Statement

M.J.M is now an employee of AstraZeneca plc

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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-NC-ND 4.0 International license.
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Posted November 05, 2020.
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GAK and PRKCD are positive regulators of PRKN-independent mitophagy
Michael J. Munson, Benan J. Mathai, Laura Trachsel, Matthew Yoke Wui Ng, Laura Rodriguez de la Ballina, Sebastian W. Schultz, Yahyah Aman, Alf H. Lystad, Sakshi Singh, Sachin Singh, Jørgen Wesche, Evandro F. Fang, Anne Simonsen
bioRxiv 2020.11.05.369496; doi: https://doi.org/10.1101/2020.11.05.369496
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GAK and PRKCD are positive regulators of PRKN-independent mitophagy
Michael J. Munson, Benan J. Mathai, Laura Trachsel, Matthew Yoke Wui Ng, Laura Rodriguez de la Ballina, Sebastian W. Schultz, Yahyah Aman, Alf H. Lystad, Sakshi Singh, Sachin Singh, Jørgen Wesche, Evandro F. Fang, Anne Simonsen
bioRxiv 2020.11.05.369496; doi: https://doi.org/10.1101/2020.11.05.369496

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