Unraveling the Multifaceted Role of TRIM21 in Virus-Triggered Innate Immunity and Diseases

Tripartite motif-containing protein 21 (TRIM21/Ro52) is a pivotal E3 ubiquitin ligase and cytoplasmic fragment crystallizable receptor (FcR). It plays a crucial role in viral infections, autoimmune disorders, and cancers by regulating multiple cell signaling axes, including the NF-κB, RIG-I-like receptor (RLR), cGAS-STING, and Toll-like receptor (TLR) pathways. Type I interferon (IFN-I), a pleiotropic cytokine, is produced via these immune signaling pathways, which are often triggered by viral components. TRIM21 both activates IFN-I signaling and mediates its negative feedback through post-translational modification of key immune signaling proteins, thereby maintaining immune homeostasis. In recent years, TRIM21 has been found to dually regulate autophagy and IFN-I in the context of virus–host interplay. Herein, we systematically summarize the functional roles of TRIM21 in virus-triggered intracellular immunity, aiming to provide insights for researchers and inspire further investigation in this area.