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.
Highlights
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
The process of autophagy is executed by autophagy-related genes (ATGs) proteins (ULK1, Belcin[1], ATG3/5/7/12, LC3, etc.) and is regulated by several signaling pathways, including mTORC1 and AMPK, as well as by epigenetic changes2–4. mTOR is one of the most important pathways that negatively regulates autophagy in mammalian cells1. mTORC1 inhibits ULK1-dependent autophagy by phosphorylating ULK1 at serine 7575. mTORC1 suppresses autophagy by phosphorylating and inhibiting nuclear translocation of the transcription factor EB (TFEB), which promotes the transcription of lysosomal biogenesis and the autophagic process[6]
By identifying ENDOG as a phosphorylation substrate of GSK-3β and the interaction between ENDOG and 14-3-3γ, we reveal that GSK-3β mediated phosphorylation of ENDOG enhances its interaction with 14-3-3γ, leading to the release of TSC2 and Vps[34] from 14-3-3γ, and eventually promotes mTOR pathway suppression and autophagy initiation
Summary
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. 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. 14-3-3 proteins bind and regulate TSC2 (Tuberin) and PRAS40 (Proline-rich AKT1 substrate 1), which can activate mTORC1, resulting in the inhibition of autophagy[7,8]. By identifying ENDOG as a phosphorylation substrate of GSK-3β (glycogen synthase kinase 3 beta) and the interaction between ENDOG and 14-3-3γ, we reveal that GSK-3β mediated phosphorylation of ENDOG enhances its interaction with 14-3-3γ, leading to the release of TSC2 and Vps[34] from 14-3-3γ, and eventually promotes mTOR pathway suppression and autophagy initiation. Our study shed light on the molecular mechanisms for the physiologic function of ENDOG during autophagy
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