PUBLICATION
GAK and PRKCD are positive regulators of PRKN-independent mitophagy
- Authors
- Munson, M.J., Mathai, B.J., Ng, M.Y.W., Trachsel-Moncho, L., de la Ballina, L.R., Schultz, S.W., Aman, Y., Lystad, A.H., Singh, S., Singh, S., Wesche, J., Fang, E.F., Simonsen, A.
- ID
- ZDB-PUB-211025-4
- Date
- 2021
- Source
- Nature communications 12: 6101 (Journal)
- Registered Authors
- Lystad, Alf Hakon, Mathai, Benan John, Ng, Matthew, Simonsen, Anne
- Keywords
- none
- MeSH Terms
-
- Animals
- Autophagy
- Autophagy-Related Protein-1 Homolog/metabolism
- Autophagy-Related Proteins/metabolism
- Caenorhabditis elegans
- Cell Line, Tumor
- Deferiprone/pharmacology
- Fatty Acid-Binding Proteins/genetics
- Fatty Acid-Binding Proteins/metabolism
- Humans
- Intracellular Signaling Peptides and Proteins/antagonists & inhibitors
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism*
- Lysosomes/metabolism
- Mitochondria/metabolism
- Mitophagy*/drug effects
- Protein Kinase C-delta/antagonists & inhibitors
- Protein Kinase C-delta/genetics
- Protein Kinase C-delta/metabolism*
- Protein Serine-Threonine Kinases/antagonists & inhibitors
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism*
- Zebrafish
- PubMed
- 34671015 Full text @ Nat. Commun.
Citation
Munson, M.J., Mathai, B.J., Ng, M.Y.W., Trachsel-Moncho, L., de la Ballina, L.R., Schultz, S.W., Aman, Y., Lystad, A.H., Singh, S., Singh, S., Wesche, J., Fang, E.F., Simonsen, A. (2021) GAK and PRKCD are positive regulators of PRKN-independent mitophagy. Nature communications. 12:6101.
Abstract
The mechanisms involved in programmed or damage-induced removal of mitochondria by mitophagy 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 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 facilitates recruitment of ULK1/ATG13 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 knockout of PRKCD homologues in zebrafish led to significant inhibition of basal mitophagy, highlighting the evolutionary relevance of these kinases in mitophagy regulation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping