Dysfunction of TRIM21 in interferon signature of systemic lupus erythematosus

Abstract

Objectives: TRIM21 is an E3 ubiquitin ligase for interferon regulatory factors (IRFs) that are involved in innate and acquired immunity. Here, we evaluated the role of TRIM21 in the interferon (IFN) signature of systemic lupus erythematosus (SLE).

Methods: Twenty SLE patients and 24 healthy controls were enrolled in this study. We analyzed mRNA expression of TRIM21, type I IFN, and IFN-inducible genes in peripheral blood mononuclear cell (PBMC). The protein levels of IRFs were assessed by Western blotting in PBMCs cultured with or without MG-132.

Results: The expression of TRIM21 mRNA and protein was significantly higher in SLE PBMCs as compared to healthy controls. There was a correlation between TRIM21 mRNA expression and SLE activities. In contrast to a negative correlation between mRNA expression level of TRIM21 and those of type I IFNs in healthy controls, we found a positive correlation between them in anti-TRIM21 antibody-positive SLE patients. Neither positive nor negative correlation was observed in the autoantibody-negative SLE patients. Western-blotting analysis revealed impaired ubiquitin-dependent proteasomal degradation of IRFs in SLE PBMCs.

Conclusion: Our study showed ubiquitin-dependent proteasomal degradation of IRFs was impaired in anti-TRIM21 antibody-dependent and -independent fashions, leading to amplification of IFN signature in SLE.

Keywords:

• E3 ubiquitin ligase
• interferon signature
• IRF
• systemic lupus erythematosus
• TRIM21

Acknowledgments

We thank all the colleagues in our laboratories for kind cooperation in this project. We also thank Mr. Tom Kiper for his review of this article.

Conflict of interest

None.

Additional information

Funding

This work was supported by JSPS KAKENHI [Grant No. JP23791118, JP26461468 (to R.Y.), JP25461479 (Y.A.), JP26713036 and JP15K15374 (Y.K.)], the Japan Rheumatism Foundation (R.Y.), Yokohama Foundation for Advancement of Medical Science (R.Y., Y.K.), the Takeda Science Foundation (R.Y., Y.K.), Kanae Foundation.(Y.K.). This study was partly supported by a grant from Bristol-Myers K.K. (R.Y.).