RT Journal Article
SR Electronic
T1 GAK and PRKCD are positive regulators of PRKN-independent mitophagy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.05.369496
DO 10.1101/2020.11.05.369496
A1 Michael J. Munson
A1 Benan J. Mathai
A1 Laura Trachsel
A1 Matthew Yoke Wui Ng
A1 Laura Rodriguez de la Ballina
A1 Sebastian W. Schultz
A1 Yahyah Aman
A1 Alf H. Lystad
A1 Sakshi Singh
A1 Sachin Singh
A1 Jørgen Wesche
A1 Evandro F. Fang
A1 Anne Simonsen
YR 2020
UL http://biorxiv.org/content/early/2020/11/05/2020.11.05.369496.abstract
AB 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 StatementM.J.M is now an employee of AstraZeneca plc