Itch attenuates CD4 T‐cell proliferation in mice by limiting WBP2 protein stability

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.

WBP2 promotes BTRC mRNA stability to drive migration and invasion in triple‐negative breast cancer via NF‐κB activation

“…In conclusion, we demonstrated that WBP2 drives TNBC migration and invasion under TNF‐α‐induced conditions, which mimic the tumor‐stimulatory microenvironment. Although previous studies hinted the possible involvement of WBP2 in inflammation, via its binding to ITCH [17,82], a negative regulator of TNF/NF‐κB signaling, this study shows for the first time a participatory role of WBP2 in tumor inflammatory signaling, particularly in TNF/NF‐κB signaling pathway. Moreover, its regulation on BTRC mRNA stability highlights an alternative mode of action of WBP2 as a posttranscriptional regulator, besides its widely reported functional role as a transcriptional coactivator.…”

The E3 ubiquitin ligase Cul4b promotes CD4+ T cell expansion by aiding the repair of damaged DNA

“…GOplot algorithm was employed to visualize the gene ontology analysis results [ 92 ]. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [ 93 ] partner repository with the data set identifier PXD017699 and PXD019272 [ 94 ].…”

WW domain binding protein 2 (WBP2) as an oncogene in breast cancer: mechanisms and therapeutic prospects—a narrative review

“…In the endocrine system, WBP2 can be involved in insulin signaling and lipid metabolism (29,30) and may also be involved in thyroid differentiation in conjunction with Pax8 (16). More than that, WBP2 can also be promoted to degradation by itchy E3 ubiquitin-protein ligase (ITCH) to attenuate the proliferation of CD4 + T cells and hence participate in the inflammatory response (31). In addition, WBP2 can activate oocytes, and takes the same position as WW binding protein 2 N-terminal like (WBP2NL) in mouse sperm (32).…”