Itch attenuates CD4 T‐cell proliferation in mice by limiting WBP2 protein stability
- 9 June 2020
- journal article
- research article
- Published by Wiley in European Journal of Immunology
- Vol. 50 (10), 1468-1483
- https://doi.org/10.1002/eji.201948323
Abstract
To mount an anti‐pathogen 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 co‐activator 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. This article is protected by copyright. All rights reservedKeywords
Funding Information
- National Institute of Allergy and Infectious Diseases (R01AI093566, R01AI114515)
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