GSK3B induces autophagy by phosphorylating ULK1

• Published in: Experimental & molecular medicine 2021, 53(0), , pp.1-15
• Main Authors: Ryu, Hye Young, Kim, Leah Eunjung, Jeong, Hyeonjeong, Yeo, Bo Kyoung, Lee, Ji-Won, Nam, Hyeri, Ha, Shinwon, An, Hyun-Kyu, Park, Hyunhee, Jung, Seonghee, Chung, Kyung Min, Kim, Jiyea, Lee, Byung-Hoon, Cheong, Heesun, Kim, Eun-Kyoung, Yu, Seong-Woon
• Format: Article
• Language: English
• Subjects: 13/89; 13/95; 14/19; 45/70; 631/80/39/2346; 631/80/458/1733; 82/1; 96/100; 96/106; 96/35; Acetylation; Animals; Autophagy; Autophagy-Related Protein-1 Homolog - genetics; Autophagy-Related Protein-1 Homolog - metabolism; Biomedical and Life Sciences; Biomedicine; Defective mutant; Enzymes; GABARAP protein; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - metabolism; Hippocampus; Hippocampus - metabolism; Hippocampus - pathology; Insulin; Kinases; Medical Biochemistry; Molecular Medicine; Neural stem cells; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Pancreatic cancer; Phagocytosis; Phosphorylation; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Signal Transduction; Stem Cells; Tumor cell lines; Tumorigenesis; Ubiquitination; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-021-00570-6

Unc-51-like autophagy activating kinase 1 (ULK1), a mammalian homolog of the yeast kinase Atg1, has an essential role in autophagy induction. In nutrient and growth factor signaling, ULK1 activity is regulated by various posttranslational modifications, including phosphorylation, acetylation, and ubiquitination. We previously identified glycogen synthase kinase 3 beta (GSK3B) as an upstream regulator of insulin withdrawal-induced autophagy in adult hippocampal neural stem cells. Here, we report that following insulin withdrawal, GSK3B directly interacted with and activated ULK1 via phosphorylation of S405 and S415 within the GABARAP-interacting region. Phosphorylation of these residues facilitated the interaction of ULK1 with MAP1LC3B and GABARAPL1, while phosphorylation-defective mutants of ULK1 failed to do so and could not induce autophagy flux. Furthermore, high phosphorylation levels of ULK1 at S405 and S415 were observed in human pancreatic cancer cell lines, all of which are known to exhibit high levels of autophagy. Our results reveal the importance of GSK3B-mediated phosphorylation for ULK1 regulation and autophagy induction and potentially for tumorigenesis. Cell biology: Modified enzyme implicated in tumor formation Similar to cellular starvation conditions, insulin withdrawal may trigger the modification of an enzyme involved in the induction of autophagy, a key cellular recycling process. The ULK1 enzyme has a critical role in autophagy induction. Seong-Woon Yu at the Daegu Gyeongbuk Institute of Science and Technology, South Korea, and co-workers investigated how ULK1 is activated under insulin withdrawal condition. They found that another enzyme called GSK3B modifies two specific ULK1 amino acids, activating ULK1 and triggering autophagy. Further, they found high levels of this type of ULK1 modification in human pancreatic cancer cell lines that exhibited increased autophagy, suggesting possible implications for the development of certain cancerous tumors.