TY - JOUR
T1 - GSK3B induces autophagy by phosphorylating ULK1
AU - Ryu, Hye Young
AU - Kim, Leah Eunjung
AU - Jeong, Hyeonjeong
AU - Yeo, Bo Kyoung
AU - Lee, Ji-Won
AU - Nam, Hyeri
AU - Ha, Shinwon
AU - An, Hyun-Kyu
AU - Park, Hyunhee
AU - Jung, Seonghee
AU - Chung, Kyung Min
AU - Kim, Jiyea
AU - Lee, Byung-Hoon
AU - Cheong, Heesun
AU - Kim, Eun-Kyoung
AU - Yu, Seong-Woon
N1 - Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.
PY - 2021/3/2
Y1 - 2021/3/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85102083101&partnerID=8YFLogxK
U2 - 10.1038/s12276-021-00570-6
DO - 10.1038/s12276-021-00570-6
M3 - Article
C2 - 33654220
SN - 1226-3613
VL - 53
SP - 369
EP - 383
JO - Experimental and Molecular Medicine
JF - Experimental and Molecular Medicine
IS - 3
ER -