Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy

JP Bernardini; JM Brouwer; IKL Tan; JJ Sandow; S Huang; CA Stafford; A Bankovacki; CD Riffkin; AZ Wardak; PE Czabotar; M Lazarou; G Dewson

Journal article

Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy

JP Bernardini, JM Brouwer, IKL Tan, JJ Sandow, S Huang, CA Stafford, A Bankovacki, CD Riffkin, AZ Wardak, PE Czabotar, M Lazarou, G Dewson

EMBO Journal | WILEY | Published : 2019

DOI: 10.15252/embj.201899916

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Abstract

The E3 ubiquitin ligase Parkin is a key effector of the removal of damaged mitochondria by mitophagy. Parkin determines cell fate in response to mitochondrial damage, with its loss promoting early onset Parkinson's disease and potentially also cancer progression. Controlling a cell's apoptotic response is essential to co-ordinate the removal of damaged mitochondria. We report that following mitochondrial damage-induced mitophagy, Parkin directly ubiquitinates the apoptotic effector protein BAK at a conserved lysine in its hydrophobic groove, a region that is crucial for BAK activation by BH3-only proteins and its homo-dimerisation during apoptosis. Ubiquitination inhibited BAK activity by im..

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University of Melbourne Researchers

Peter Czabotar Author

Michael Lazarou Author

Grant Dewson Author

Grants

Awarded by Cancer Therapeutics Cooperative Research Centre

Funding Acknowledgements

We thank B. Reljic and M. Ryan for providing the VDAC2 antibody, D.C.S. Huang and D. Segal for cell lines and K. Scicluna for assistance with the manuscript. We thank Dario Altieri (Wistar Institute Cancer Center, Philadelphia) for the mitochondrial Hsp90 inhibitor GTPP. J.P.B. is supported by an Australian Government Research Training Program Scholarship and a Cancer Therapeutics CRC PhD Top Up Scholarship. M.L. is supported by the National Health and Medical Research Council (GNT1106471), and a fellowship from the Australian Research Council (FT160100063). P.E.C is supported by a fellowship from the National Health and Medical research Council (1079700). This work was supported by grants from the National Health and Medical Research Council (1078924), a fellowship from the Australian Research Council (FT100100791 to G.D.) and operational infrastructure grants through the Australian Government IRISS and the Victorian State Government OIS 9000220.