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

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

  • Cell Death Differ. 2022 Jan;29(1):1-13. doi: 10.1038/s41418-021-00827-7.
Ping Liu  # 1,  Xiaoji Cong  # 1 2,  Shengjie Liao  # 3,  Xinglong Jia  # 1,  Xiaomin Wang 2 4,  Wei Dai 5,  Linhui Zhai 1,  Lei Zhao 1,  Jing Ji 6,  Duan Ni 7,  Zhiwei Liu 1 2,  Yulu Chen 3,  Lulu Pan 1 2,  Wei Liu 6,  Jian Zhang 7 8,  Min Huang 2 4,  Bin Liu 9 10,  Minjia Tan 11 12
Affiliations

Affiliations

  • 1 Chemical Proteomics Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 2 University of Chinese Academy of Sciences, Beijing, China.
  • 3 Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Huangshi, Hubei, China.
  • 4 Division of Antitumor pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 5 Center for Information Technology, School of Economics and Management, Hubei Polytechnic University, Huangshi, Hubei, China.
  • 6 Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China.
  • 7 State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 8 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.
  • 9 Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Huangshi, Hubei, China. liubin@jou.edu.cn.
  • 10 Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China. liubin@jou.edu.cn.
  • 11 Chemical Proteomics Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. mjtan@simm.ac.cn.
  • 12 University of Chinese Academy of Sciences, Beijing, China. mjtan@simm.ac.cn.
  • # Contributed equally.
PMID: 34215846 DOI: 10.1038/s41418-021-00827-7
Abstract

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 SCFFBXO22 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 SCFFBXO22. 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.

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