Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy
Jonathan P Bernardini, Jason M Brouwer, Iris KL Tan, Jarrod J Sandow, Shuai Huang, Che A Stafford, Aleksandra Bankovacki, Christopher D Riffkin, Ahmad Z Wardak, Peter E Czabotar, Michael Lazarou, Grant Dewson
The EMBO Journal | WILEY | Published : 2019
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..View full abstract
Awarded by National Health and Medical Research Council
Awarded by Australian Research Council
Awarded by Victorian State Government
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.