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
  • 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. [email protected].
  • 10. Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China. [email protected].
  • 11. Chemical Proteomics Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 12. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • # 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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