Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy
Details
Publication Year 2019-01-15, Volume 38, Issue #2, Page pii: e99916
Journal Title
EMBO Journal
Publication Type
Journal Article
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 impairing its activation and the formation of lethal BAK oligomers. Parkin also suppresses BAX-mediated apoptosis, but in the absence of BAX ubiquitination suggesting an indirect mechanism. In addition, we find that BAK-dependent mitochondrial outer membrane permeabilisation during apoptosis promotes PINK1-dependent Parkin activation. Hence, we propose that Parkin directly inhibits BAK to suppress errant apoptosis, thereby allowing the effective clearance of damaged mitochondria, but also promotes clearance of apoptotic mitochondria to limit their potential pro-inflammatory effect.
Publisher
EMBO Press
WEHI Research Division(s)
Ubiquitin Signalling; Advanced Technology And Biology; Blood Cells And Blood Cancer; Structural Biology
PubMed ID
30573668
NHMRC Grants
NHMRC/GNT1106471 NHMRC/1078924
ARC Grants
ARC/FT100100791,
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2020-01-21 11:05:26
Last Modified: 2020-02-03 09:31:10
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