Updated project metadata. DUSP22 (also named JKAP) is a dual-specificity phosphatase that inhibits T cell activation. Here we identified the E3 ubiquitin ligase UBR2 as an upstream activator of Lck during T-cell activation. JKAP dephosphorylated UBR2 at two residues, leading to ubiquitin-mediated UBR2 degradation. The SCF (SKP1-CUL1-βTrCP) complex induced UBR2 Lys48-linked ubiquitination at three lysine residues. Moreover, single-cell RNA sequencing analysis and UBR2 knockout showed that UBR2 increased proinflammatory cytokines. Remarkably, UBR2 induced Lys63-linked ubiquitination of Lck at two lysine residues and subsequent Lck Tyr394 phosphorylation/activation in TCR signaling. Conversely, TCR-induced Lck activation and JKAP knockout-enhanced inflammatory phenotypes were attenuated by UBR2 knockout. Consistently, the UBR2- Lck interaction and Lck Lys63-linked ubiquitination were induced in peripheral blood T cells of human SLE patients. Collectively, UBR2 protein stability and UBR2-induced Lck ubiquitination/activation are inhibited by JKAP, leading to attenuation of T-cell activation and T-cell-mediated inflammation.