Itch attenuates CD4 T‐cell proliferation in mice by limiting WBP2 protein stability. Issue 10 (9th June 2020)

• Record Type: Journal Article
• Authors: Field, Natania S.; Elbulok, Omar A.; Dybas, Joseph M.; Moser, Emily K.; Dar, Asif A.; Spruce, Lynn A.; Fazelinia, Hossein; Seeholzer, Steven H.; Oliver, Paula M.
• Is Part Of: European journal of immunology. Volume 50:Issue 10(2020)
• Page Start: 1468
• Page End: 1483
• Publication Date: 2020-06-09
• Subjects: Autoinflammation -- Cell cycle -- E3 ubiquitin ligase -- Proliferation; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201948323
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: To mount an antipathogen response, CD4 T cells must undergo rapid cell proliferation; however, poorly controlled expansion can result in diseases such as autoimmunity. One important regulator of T‐cell activity is the E3 ubiquitin ligase Itch. Itch deficient patients suffer from extensive autoinflammation. Similarly, Itch deficient mice exhibit inflammation characterized by high numbers of activated CD4 T cells. While the role of Itch in limiting CD4 T‐cell cytokine production has been extensively studied, it is less clear whether and how Itch regulates proliferation of these cells. We determined that Itch deficient CD4 T cells are hyperproliferative in vitro and in vivo, due to increased S phase entry. Whole cell proteomics analysis of Itch deficient primary mouse CD4 T cells revealed increased abundance of the β‐catenin coactivator WW domain‐binding protein 2 (WBP2). Furthermore, Itch deficient cells demonstrate increased WBP2 protein stability, and Itch and WBP2 interact in CD4 T cells. Knockdown of WBP2 in CD4 T cells caused reduced proliferation. Together, our data support that Itch attenuates CD4 T cell proliferation by promoting WBP2 degradation. This study identifies novel roles for Itch and WBP2 in regulating CD4 T cell proliferation, providing insight into how Itch may prevent inflammation. Abstract : In mouse CD4 T cells, Itch binds to WBP2 and promotes its degradation. In the absence of Itch, WBP2 accumulates, and cells are more likely to enter S phase and proliferate.