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The ubiquitin E3 ligase TRIM21 suppresses type I interferon signaling via STING degradation and ameliorates systemic
Da Som Kim1,2, Youngjae Park3, George C Tsokos4
1The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Abstract:
Tripartite motif-containing 21 (TRIM21) is a cytoplasmic protein with E3 ubiquitin ligase activity. Although autoantibodies against TRIM21 are frequently detected in patients with systemic lupus erythematosus (SLE), its role in disease pathogenesis remains unclear. Here we demonstrate that TRIM21 directly interacts with the stimulator of interferon genes (STING) to regulate type I interferon (IFN) production. In both induced and spontaneous murine models of lupus, TRIM21 deficiency exacerbated lupus-like pathology and heightened IFN production after STING activation. By contrast, TRIM21 overexpression attenuated autoimmunity in lupus-prone mice. Mechanistically, TRIM21 binds to STING and promotes its degradation via the ubiquitin-proteasome pathway. In patients with SLE, TRIM21 expression levels inversely correlated with STING expression, type I IFN levels and autoantibody titers. These findings suggest that targeting the TRIM21-STING axis may offer a therapeutic strategy to reduce type I IFN production in SLE.
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