Background/Purpose: Although the increased expression of type I interferon (IFN)-inducible genes, called “IFN signature”, has been suggested to have important roles in the pathogenesis of systemic lupus erythematosus (SLE), its mechanism still remains unclear. Recent studies in vitro or with mice suggest that tripartite motif-containing 21 (TRIM21), an autoantigen also called Ro52 or SSA1, is involved in the regulation of type I IFN production as an E3 ubiquitin ligase for IFN regulatory factors (IRF). Here, we investigated the pathological role of TRIM21 in SLE.

Methods: We collected peripheral blood mononuclear cells (PBMC) from 20 patients who met the 1997 ACR SLE classification criteria and 24 healthy controls (HC), and analyzed the mRNA expression of TRIM21, type I IFNs, type I IFN-inducible genes by qPCR. We also quantified protein levels of TRIM21 and IRF proteins in the PBMC from SLE patients and HC by Western blot analysis. To evaluate the degree of ubiquitylation of IRF proteins, PBMC were incubated with a proteasome inhibitor MG-132.

Results: There were no significant differences in age and sex ratio between patients with SLE and HC (41.2 ± 13.9 vs 34.1 ± 10.4 years, p = 0.09, and 67% vs 75% (female), p = 0.73, respectively). Seven patients (35%) with SLE had anti-TRIM21 autoantibody while all of HC were negative for anti-TRIM21 antibody. The mRNA and protein levels of TRIM21 were significantly higher in PBMC from patients with SLE as compared to HC. Although transcript levels of multiple genes including MX1, IFI27, IFI44 and SIGLEC1, known as type IFN-inducible genes, were significantly higher in patients with SLE as compared to HC, there was no significant difference in mRNA levels of type I IFNs themselves between SLE and HC. In HC, IFN-α and IFN-β mRNA levels were negatively correlated with the level of TRIM21 transcript (r = -0.52, p = 0.0087, and r = -0.48, p = 0.018, respectively). On the other hand, there was no significant correlation between TRIM21 transcript level and IFN-α mRNA (r = 0.21, p = 0.37) or IFN-β mRNA level (r = 0.24, p = 0.30) in SLE. To investigate the degrees of ubiquitylation of IRF proteins, PBMC from patients with SLE and HC were incubated with MG-132. Although the protein expression levels of IRF3 and IRF5 were significantly increased by MG-132 in PBMC from HC, the effect of MG-132 was not observed in PBMC from SLE patients.

Conclusion: This study suggests that dysregulation of E3 ubiquitin ligase activity of TRIM21 for IRF proteins may be associated with the increased expression of type I IFN-inducible genes in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-role-of-tripartite-motif-containing-21-in-interferon-signature-of-systemic-lupus-erythematosus/