Protein phosphorylation-acetylation cascade connects growth factor deprivation to autophagy.
Different from unicellular organisms, metazoan cells require the presence of extracellular growth factors to utilize environmental nutrients. However, the underlying mechanism was unclear. We have delineated a pathway, in which glycogen synthase kinase 3 (GSK3) in cells deprived of growth factors phosphorylates and activates the acetyltransferase KAT5/TIP60, which in turn stimulates the protein kinase ULK1 to elicit autophagy. Cells with the Kat5/Tip60 gene replaced with Kat5(S86A) that cannot be phosphorylated by GSK3 are resistant to serum starvation-induced autophagy. Acetylation sites on ULK1 were mapped to K162 and K606, and the acetylation-defective mutant ULK1(K162,606R) displays reduced kinase activity and fails to rescue autophagy in Ulk1(-/-) mouse embryonic fibroblasts, indicating that acetylation is vital to the activation of ULK1. The GSK3-KAT5-ULK1 cascade seems to be specific for cells to sense growth factors, as KAT5 phosphorylation is not enhanced under glucose deprivation. Distinct from the glucose starvation-autophagy pathway that is conserved in all eukaryotic organisms, the growth factor deprivation response pathway is perhaps unique to metazoan organisms.
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China.
Shu-Yong
SY
Lin
Terytty Yang
TY
Li
Qing
Q
Liu
Cixiong
C
Zhang
Xiaotong
X
Li
Yan
Y
Chen
Shi-Meng
SM
Zhang
Guili
G
Lian
Qi
Q
Liu
Ka
K
Ruan
Zhen
Z
Wang
Chen-Song
CS
Zhang
Kun-Yi
KY
Chien
Jiawei
J
Wu
Qinxi
Q
Li
Jiahuai
J
Han
Sheng-Cai
SC
Lin
D000107:Acetylation; D000818:Animals; D001343:Autophagy; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
D036341:Intercellular Signaling Peptides and Proteins