Global identification of phospho-dependent SCF substrates reveals a FBXO22 phosphodegron and an ERK-FBXO22-BAG3 axis in tumorigenesis

• Published in: Cell death and differentiation Vol. 29; no. 1; pp. 1 - 13
• Main Authors: Liu, Ping, Cong, Xiaoji, Liao, Shengjie, Jia, Xinglong, Wang, Xiaomin, Dai, Wei, Zhai, Linhui, Zhao, Lei, Ji, Jing, Ni, Duan, Liu, Zhiwei, Chen, Yulu, Pan, Lulu, Liu, Wei, Zhang, Jian, Huang, Min, Liu, Bin, Tan, Minjia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2022; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/2; 13/31; 631/337/475; 631/45/474/582; 64/60; 82/16; 82/58; 82/81; Adaptor Proteins, Signal Transducing - metabolism; Apoptosis; Apoptosis Regulatory Proteins - metabolism; Biochemistry; Biomedical and Life Sciences; Carcinogenesis; Cell Biology; Cell cycle; Cell Cycle Analysis; Cell Transformation, Neoplastic; Extracellular signal-regulated kinase; F-Box Proteins - genetics; F-Box Proteins - metabolism; Hsp70 protein; Humans; Life Sciences; Phosphorylation; Receptors, Cytoplasmic and Nuclear - metabolism; Stem Cells; Tumorigenesis; Ubiquitin; Ubiquitin - metabolism; Ubiquitination
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-021-00827-7

SKP1-CUL1-F-box (SCF) ubiquitin ligases play fundamental roles in cellular functions. Typically, substrate phosphorylation is required for SCF recognition and subsequent degradation. However, phospho-dependent substrates remain largely unidentified. Here, using quantitative phoshoproteome approach, we performed a system-wide investigation of phospho-dependent SCF substrates. This strategy identified diverse phospho-dependent candidates. Biochemical verification revealed a mechanism by which SCF FBXO22 recognizes the motif XXPpSPXPXX as a conserved phosphodegron to target substrates for destruction. We further demonstrated BAG3, a HSP70 co-chaperone, is a bona fide substrate of SCF FBXO22 . FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BAG3 phosphorylation at S377. FBXO22 depletion or expression of a stable BAG3 S377A mutant promotes tumor growth via defects in apoptosis and cell cycle progression in vitro and in vivo. In conclusion, our study identified broad phosphorylation-dependent SCF substrates and demonstrated a phosphodegron recognized by FBXO22 and a novel ERK-FBXO22-BAG3 axis involved in tumorigenesis.