2. Academic Validation
  3. A STUB1 ubiquitin ligase/CHIC2 protein complex negatively regulates the IL-3, IL-5, and GM-CSF cytokine receptor common β chain (CSF2RB) protein stability

A STUB1 ubiquitin ligase/CHIC2 protein complex negatively regulates the IL-3, IL-5, and GM-CSF cytokine receptor common β chain (CSF2RB) protein stability

  • J Biol Chem. 2022 Sep 12;102484. doi: 10.1016/j.jbc.2022.102484.
Sebastian H J Koochaki 1,  Mikołaj Słabicki 2,  Ryan Lumpkin 3,  Charles Zou 4,  Roger Belizaire 4,  Eric S Fischer 5,  Benjamin L Ebert 6
Affiliations

Affiliations

  • 1 Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard-MIT MD/PhD Program, Harvard Medical School, Boston, MA 02215, USA.
  • 2 Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
  • 6 Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: benjamin_ebert@dfci.harvard.edu.
PMID: 36108743 DOI: 10.1016/j.jbc.2022.102484
Abstract

The IL-3, IL-5, and GM-CSF family of cytokines plays an essential role in the growth, differentiation, and effector functions of multiple hematopoietic cell types. Receptors in this family are composed of cytokine-specific α chains and a common β chain (CSF2RB), responsible for the majority of downstream signaling. CSF2RB abundance and stability influence the magnitude of the cellular response to cytokine stimulation, but the exact mechanisms of regulation are not well understood. Here, we use genetic screens in multiple cellular contexts and cytokine conditions to identify STUB1, an E3 ubiquitin Ligase, and CHIC2 as regulators of CSF2RB ubiquitination and protein stability. We demonstrate that Stub1 and Chic2 form a complex that binds Csf2rb, and that genetic inactivation of either Stub1 or Chic2 leads to reduced ubiquitination of Csf2rb. The effects of Stub1 and Chic2 on Csf2rb were greatest at reduced cytokine concentrations, suggesting that Stub1/Chic2-mediated regulation of Csf2rb is a mechanism of reducing cell-surface accumulation when cytokine levels are low. Our study uncovers a mechanism of CSF2RB regulation through ubiquitination and lysosomal degradation and describes a role for CHIC2 in the regulation of a cytokine receptor.

Keywords

CHIC2; CSF2RB; E3 ubiquitin ligase; GM-CSF; IL-3; IL-5; STUB1; cell-surface receptor; cytokine; cytokine signaling; protein degradation; protein stability; receptor; signaling; ubiquitin; ubiquitin ligase.

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