Background Tripartite motif-containing protein (TRIM) 21 is an E3 ubiquitin-protein ligase, involved in the ubiquitin-dependent proteolysis pathway of various proteins including factors related to type I interferon pathways. Although the presence of autoantibodies against TRIM21 in various autoimmune diseases suggests potential pathogenetic roles, no studies have clarified its exact implications, especially in lupus. We aimed to elucidate the functions of TRIM21 in the dysregulation of type I interferon signals in lupus.
Methods To investigate the effects of TRIM21 dysfunction in lupus pathogenesis, two independent lupus animal models, the R848-induced model and the B6/lpr mice model were performed using TRIM21 knockout mice, and their phenotypes and immunological profiles were determined. In addition, we investigated the degree of TRIM21 dysfunction and therapeutic effects of in vivo delivery of TRIM21 in MRL/lpr mice. To evaluate the E3 ubiquitin ligase activity of TRIM21 for targeted proteins in type I interferon pathways, we performed a specialized immunoblot assay.
Results The R848 induced model and the B6/lpr model both presented with more severe lupus-like phenotypes such as nephritis, lymphadenopathies, and inflammatory immune cell profiles in TRIM21 knockout mice than in control mice. TRIM21 deficiency resulted in activation of intracellular factors related to type I interferon pathways such as STING, TBK1, and IRF3 in both models. MRL/lpr mice presented with activation of type I interferon pathways including STING, TBK1, and IRF3, and decreased expressions of TRIM21. Overexpression of TRIM21 attenuated the disease phenotypes in MRL/lpr mice. Using immunoblot assay, we observed E3 ubiquitin ligase activity of TRIM21 directly targeting STING via the proteasome pathway.
Conclusions TRIM21 dysfunction induces dysregulation of STING-type I interferon pathways and exacerbates the disease in lupus animal models. Targeting TRIM21-STING-type I interferon axis can be a novel therapeutic strategy in lupus treatment.
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