2. Academic Validation
  3. Endonuclease G promotes autophagy by suppressing mTOR signaling and activating the DNA damage response

Endonuclease G promotes autophagy by suppressing mTOR signaling and activating the DNA damage response

  • Nat Commun. 2021 Jan 20;12(1):476. doi: 10.1038/s41467-020-20780-2.
Wenjun Wang  # 1 2 3,  Jianshuang Li  # 2 3,  Junyang Tan 3,  Miaomiao Wang 3,  Jing Yang 3,  Zhi-Min Zhang 4,  Chuanzhou Li 5,  Alexei G Basnakian 6,  Hong-Wen Tang 7 8,  Norbert Perrimon 8 9,  Qinghua Zhou 10 11 12
Affiliations

Affiliations

  • 1 The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, 510632, China.
  • 2 Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, 519000, China.
  • 3 The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, 510632, China.
  • 4 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou, Guangdong, 510632, China.
  • 5 Department of Medical Genetics, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 6 Department of Pharmacology & Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
  • 7 Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
  • 8 Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.
  • 9 Howard Hughes Medical Institute, Boston, MA, 02115, USA.
  • 10 The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, 510632, China. [email protected].
  • 11 Zhuhai Institute of Translational Medicine Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, 519000, China. [email protected].
  • 12 The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, 510632, China. [email protected].
  • # Contributed equally.
PMID: 33473107 DOI: 10.1038/s41467-020-20780-2
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.

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