Usp12 stabilizes the T-cell receptor complex at the cell surface during signaling

Significance We used an unbiased screening strategy to capture deubiquitylases that participate in T cell receptor signaling in primary cells under physiological settings. We identified ubiquitin-specific peptidase (Usp) 12 as a crucial component of TCR expression at the cell surface, and found supporting evidence for its function by creating an inducible genetic knockout in Jurkat cells. Using proximity-based labeling, we identified LAT and Trat1 as substrates of Usp12. In Usp12-deficient cells, both LAT and Trat1 are ubiquitin-modified and lysosomally degraded, thus down-regulating TCR surface expression. Our data define a role of Usp12 in the TCR signaling pathway for the first time, to our knowledge. These results underscore the importance of deubiquitylases in fine-tuning signaling cascades and provide a basis for the screening of small molecules to identify potential inhibitors.