TMX1, a disulfide oxidoreductase, is necessary for T cell function through regulation of CD3zeta
Chai, T.; Loh, K. M.; Weissman, I. L.
Show abstract
T cell-targeted therapies are commonly used to manage T cell hyperactivity in autoimmune disorders, graft-versus-host diseases (GVHD), and transplant rejections. However, many patients experience significant side effects or inadequate responses to current treatments, highlighting the urgent need for alternative strategies. In this study, we searched for regulators of T cells through proximity labeling with APEX2 to detect proteins interacting with CD8, a coreceptor of the T-cell receptor (TCR). This screen revealed TMX1, an ER resident transmembrane disulfide oxidoreductase, is essential for T cell cytotoxicity and NFAT, NF{kappa}B, and AP1 signaling but not cell proliferation. TMX1 deletion decreases surface TCR expression and destabilizes CD3{zeta}, a subunit of TCR complex; however, overexpression of CD3{zeta} rescues the phenotype, suggesting that TMX1 is not required for CD3{zeta} function. Mechanistically, TMX1 was found to directly engage the CxxC motif of CD3{delta}, which has been reported to be essential for proper TCR assembly and function. We hypothesize that the loss of TMX1 interaction with CD3{delta} leads to impaired TCR assembly and subsequent CD3{zeta} destabilization. These findings identify TMX1 as a novel regulator of T-cell receptor assembly and a potential target for immunosuppressive therapy.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.