Journal
CELL DEATH AND DIFFERENTIATION
Volume 29, Issue 1, Pages 1-13Publisher
SPRINGERNATURE
DOI: 10.1038/s41418-021-00827-7
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Funding
- Natural Science Foundation of China [32071432, 81872888, 81821005, 91753203, 81773018, 71473074]
- National Key RAMP
- D Program of China [2020YFE020220]
- National Science AMP
- Technology Major Project Key New Drug Creation and Manufacturing Program [2018ZX09711002-004]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA12050406]
- Shanghai Science and Technology Committee [19JC1416300]
- Innovative Research Team of High-Level Local Universities in Shanghai [SSMUZDCX20181202]
- K. C. Wong Education Foundation
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This study identified phosphorylation-dependent SCF substrates using a quantitative phosphoproteome approach, demonstrating the mechanism by which SCFFBXO22 recognizes a phosphodegron. FBXO22 was shown to mediate BAG3 ubiquitination and degradation, impacting tumor growth, apoptosis, and cell cycle progression.
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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