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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

The IL-3, IL-5, and GM-CSF family of cytokines play 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 downst...

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Autores principales: Koochaki, Sebastian H.J., Słabicki, Mikołaj, Lumpkin, Ryan, Zou, Charles, Belizaire, Roger, Fischer, Eric S., Ebert, Benjamin L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9574515/
https://www.ncbi.nlm.nih.gov/pubmed/36108743
http://dx.doi.org/10.1016/j.jbc.2022.102484
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author Koochaki, Sebastian H.J.
Słabicki, Mikołaj
Lumpkin, Ryan
Zou, Charles
Belizaire, Roger
Fischer, Eric S.
Ebert, Benjamin L.
author_facet Koochaki, Sebastian H.J.
Słabicki, Mikołaj
Lumpkin, Ryan
Zou, Charles
Belizaire, Roger
Fischer, Eric S.
Ebert, Benjamin L.
author_sort Koochaki, Sebastian H.J.
collection PubMed
description The IL-3, IL-5, and GM-CSF family of cytokines play 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.
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spelling pubmed-95745152022-10-19 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 Koochaki, Sebastian H.J. Słabicki, Mikołaj Lumpkin, Ryan Zou, Charles Belizaire, Roger Fischer, Eric S. Ebert, Benjamin L. J Biol Chem Research Article The IL-3, IL-5, and GM-CSF family of cytokines play 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. American Society for Biochemistry and Molecular Biology 2022-09-13 /pmc/articles/PMC9574515/ /pubmed/36108743 http://dx.doi.org/10.1016/j.jbc.2022.102484 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Koochaki, Sebastian H.J.
Słabicki, Mikołaj
Lumpkin, Ryan
Zou, Charles
Belizaire, Roger
Fischer, Eric S.
Ebert, Benjamin L.
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort stub1 ubiquitin ligase/chic2 protein complex negatively regulates the il-3, il-5, and gm-csf cytokine receptor common β chain (csf2rb) protein stability
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9574515/
https://www.ncbi.nlm.nih.gov/pubmed/36108743
http://dx.doi.org/10.1016/j.jbc.2022.102484
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