RRC ID 65366
Author Wang W, Li J, Tan J, Wang M, Yang J, Zhang ZM, Li C, Basnakian AG, Tang HW, Perrimon N, Zhou Q.
Title Endonuclease G promotes autophagy by suppressing mTOR signaling and activating the DNA damage response.
Journal Nat Commun
Abstract Endonuclease G (ENDOG), a mitochondrial nuclease, is known to participate in many cellular processes, including apoptosis and paternal mitochondrial elimination, while its role in autophagy remains unclear. Here, we report that ENDOG released from mitochondria promotes autophagy during starvation, which we find to be evolutionally conserved across species by performing experiments in human cell lines, mice, Drosophila and C. elegans. Under starvation, Glycogen synthase kinase 3 beta-mediated phosphorylation of ENDOG at Thr-128 and Ser-288 enhances its interaction with 14-3-3γ, which leads to the release of Tuberin (TSC2) and Phosphatidylinositol 3-kinase catalytic subunit type 3 (Vps34) from 14-3-3γ, followed by mTOR pathway suppression and autophagy initiation. Alternatively, ENDOG activates DNA damage response and triggers autophagy through its endonuclease activity. Our results demonstrate that ENDOG is a crucial regulator of autophagy, manifested by phosphorylation-mediated interaction with 14-3-3γ, and its endonuclease activity-mediated DNA damage response.
Volume 12(1)
Pages 476
Published 2021-1-20
DOI 10.1038/s41467-020-20780-2
PII 10.1038/s41467-020-20780-2
PMID 33473107
PMC PMC7817833
MeSH 14-3-3 Proteins / metabolism Animals Apoptosis Autophagy / physiology* Caenorhabditis elegans Cell Line Class III Phosphatidylinositol 3-Kinases / metabolism DNA Damage / physiology* Drosophila Endodeoxyribonucleases / genetics* Endodeoxyribonucleases / metabolism* Gene Knockout Techniques Hep G2 Cells Humans Liver / metabolism Liver / pathology Mice Mice, Knockout Mitochondria / metabolism Phosphorylation Signal Transduction / physiology* TOR Serine-Threonine Kinases / metabolism* Transcriptome Tuberous Sclerosis Complex 2 Protein / metabolism
C.elegans tm3222