GSK3B induces autophagy by phosphorylating ULK1

Abstract

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.

Protein clearance strategies for disease intervention

“…GSK-3 was initially identified as a central kinase involved in glucose metabolism, which phosphorylates glycogen synthase, insulin receptor 1, phosphoenolpyruvate carboxykinase and glucose 6-phosphatase (Embi et al 1980 ; Liberman and Eldar-Finkelman 2005 ; Lochhead et al 2001 ). Further studies reported that inhibition of GSK-3 leads to increased autophagy in distinct cell types, mainly cancer cells (Gavilán et al 2013 ; Marchand et al 2015 ; Ren et al 2018 ; Ryu et al 2021 ). Notably, the GSK-3 inhibitor L807mts enhances clearance of aggregates through elevated autophagy in SH-SY5Y cells expressing mutant HTT.…”

Suppressor of Cytokine Signaling 2 Regulates Retinal Pigment Epithelium Metabolism by Enhancing Autophagy

“…Many studies reported that GSK3β is involved in autophagy. For example, GSK3β induces autophagy by phosphorylating ULK1 ( Ryu et al, 2021 ) and C42 promotes autophagy by regulating the K-Ras/GSK3 signaling pathway in HCT116 cells ( Niu et al, 2014 ). Inhibition of GSK3β stimulated mTOR signaling and inhibited autophagy through a rapamycin-sensitive mechanism during myocardial ischemia and IR ( Zhai et al, 2011 ).…”

“…GSK3β mediates the activation of mTOR by Wnt signaling and the inhibition of GSK3β increases the activation of mTOR ( Inoki et al, 2006 ). GSK3β induces autophagy by phosphorylating unc-51 like autophagy activating kinase 1 (ULK1) in the adult hippocampal neural stem cells ( Ryu et al, 2021 ). Inhibition of long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) improves myocardial ischemia/reperfusion (I/R) injury by targeting miR-133a through inhibition of autophagy and regulation of SOCS2 ( Li et al, 2019 ).…”

GSK-3β mediates cardiac senescence through inhibition of ULK1 directed autophagy

“…Inhibition of GSK-3β is achieved through phosphorylation in Ser9. One of the principal kinases that phosphorylate GSK-3β at Ser9 is Akt/PI3K, which is phosphorylated and activated by mTORC2 [4] . Previously, GSK-3β was reported as an upstream regulator of autophagy in adult hippocampal neural stem cells through its interaction with ULK1 via phosphorylation of Ser405 and Ser415 within the GABARAPinteracting region [5] .…”

“…In the heart, GSK-3β was shown to be activated during ischemia but inhibited during reperfusion, suggesting that adaptive activation of GSK-3β during ischemia stimulates autophagy, whereas inhibition of GSK-3β inactivates autophagy during reperfusion. Inhibiting GSK-3β expression during both ischemia and reperfusion was detrimental to cardiac function [4] .…”