Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by immune system imbalance, particularly involving the overactivation of type I interferon (IFN-1) and NF-κB pathways. TRIM21, an E3 ubiquitin ligase, plays a crucial role in downregulating these pathways by targeting specific regulatory proteins for degradation via the proteasome. This study utilized an in-silico approach to assess the effects of three-point mutations—C16A, C31A, and H33A—within the essential RING finger domain of TRIM21. Protein stability analysis using I-Mutant 2.0 revealed that the C16A and C31A mutations reduced protein stability (negative ΔG) and increased binding affinity (low Kd), while the H33A mutation showed a slight increase in stability (positive ΔG) but decreased binding affinity (higher Kd). Structural visualization demonstrated that these mutations disrupted the integrity of the RING domain. These changes are predicted to impair TRIM21’s ability to regulate immune signalling, potentially resulting in uncontrolled IFN-1 and NF-κB activation—key features in SLE development. The study highlights TRIM21’s vital function in immune regulation and suggests its potential as a therapeutic target in autoimmune diseases.
Utama et al. (Tue,) studied this question.