O-GlcNAcylation increases PYGL activity by promoting phosphorylation

Author:

Chen Yan-Fang1,Zhu Jing-Jing1,Li Jing2,Ye Xin-Shan1ORCID

Affiliation:

1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xue Yuan Road, Beijing, 100191, China

2. Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, 105 Xisanhuan North Road, Beijing, 100048, China

Abstract

Abstract O-GlcNAcylation is a post-translational modification that links metabolism with signal transduction. High O-GlcNAcylation appears to be the general characteristic of cancer cells. It promotes the invasion, metastasis, proliferation and survival of tumor cells, and alters many metabolic pathways. Glycogen metabolism increases in a wide variety of tumors, suggesting that it is an important aspect of cancer pathophysiology. Herein we focused on the O-GlcNAcylation of liver glycogen phosphorylase (PYGL)—an important catabolism enzyme in the glycogen metabolism pathway. PYGL expressed in both HEK 293T and HCT116 were modified by O-GlcNAc. And both PYGL O-GlcNAcylation and phosphorylation of Ser15 (pSer15) were decreased under glucose and insulin, whereas increased under glucagon and Na2S2O4 (hypoxia) conditions. Then, we identified the major O-GlcNAcylation site to be Ser430, and demonstrated that pSer15 and Ser430 O-GlcNAcylation were mutually reinforced. Lastly, we found that Ser430 O-GlcNAcylation was fundamental for PYGL activity. Thus, O-GlcNAcylation of PYGL positively regulated pSer15 and therefore its enzymatic activity. Our results provided another molecular insight into the intricate post-translational regulation network of PYGL.

Funder

National Key Research and Development Program of China

National Natural Science Foundation of China

Beijing Outstanding Young Scientist Program

Publisher

Oxford University Press (OUP)

Subject

Biochemistry

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