DUSP22 dysregulation and UBR2 upregulation induce T-cell receptor signaling and systemic lupus erythematosus 2256861

Abstract

Abstract Introduction Downregulation of DUSP22 in peripheral blood T cells is correlated with human systemic lupus erythematosus (SLE) nephritis. DUSP22 dephosphorylates and inactivates Lck in TCR signaling, leading to suppression of autoimmune disease. We found that DUSP22 dephosphorylated E3 ubiquitin ligase UBR2, leading to its K48-linked ubiquitination and degradation. Remarkably, UBR2 induced Lck K63-linked ubiquitination, leading to Lck Tyr394 autophosphorylation and activation upon TCR signaling. The induction of proinflammatory cytokines and autoimmunity in DUSP22 KO mice was blocked by knocking out UBR2 in vivo. Furthermore, UBR2 protein levels, the UBR2-Lck interaction, and Lck K63-linked ubiquitination were induced in T cells of human SLE patients. Methods We performed NGS deep sequencing to identify DUSP22 gene variants in SLE patients from two independent cohorts, and characterized the functional consequences of the identified DUSP22 variants. Results Our NGS data revealed that 46 DUSP22 gene variants occurred in 20.79% or 18.75% SLE patients from two cohorts. Among the 46 DUSP22 variants, 6 DUSP22 somatic variants altered DUSP22 codons, and another variant was located in the DUSP22 promoter region. Moreover, 16 and 12 variants in the 3’-UTR of the DUSP22 gene were identified from Cohort #1 and Cohort #2, respectively. The functional effects of these identified DUSP22 gene variants were investigated by site-direct mutagenesis, promoter reporter assays, immunoblotting analyses, and 3’-UTR reporter assays. Interestingly, the DUSP22 promoter activity, DUSP22 protein level, or DUSP22 3’-UTR activity was reduced by individual DUSP22 gene variants. Using mass spectrometry-based proteomics, we identified an E3 ligase that induced K48-linked ubiquitination and subsequent proteasomal degradation of the DUSP22 protein. Furthermore, DUSP22 variant-knockin mice indeed spontaneously developed nephritis. Conclusion Collectively, DUSP22 deficiency and UBR2 induction play critical roles in the pathogenesis of SLE. Funding Source n/a Topic Categories Basic Autoimmunity (BA)