RBM6 Facilitates RLR-Mediated Antiviral Responses by Promoting K63-Linked Ubiquitination of MAVS.

The mitochondrial antiviral signaling protein (MAVS; also known as VISA, IPS-1, or Cardif) is the central adaptor of the RIG-I-like receptor (RLR) pathway. Upon viral infection, MAVS forms prion-like aggregates to activate NF-κB and IRF3, thereby inducing type I interferon production and antiviral responses. Here, we identify RNA-binding motif protein 6 (RBM6) as a previously unrecognized positive regulator of MAVS signaling during Sendai virus (SeV) infection. RBM6 overexpression enhanced SeV-induced IFN-β expression, whereas RBM6 deficiency impaired this response. Mechanistically, RBM6 enhanced K63-linked polyubiquitination of MAVS, promoting MAVS aggregation and facilitating the recruitment of TRAF6. Domain-mapping analysis further localized the antiviral activity of RBM6 to its zinc finger (ZnF) domain spanning residues 850-1045. Together, these findings establish RBM6 as an important enhancer of MAVS signalosome assembly and provide new insight into ubiquitin-dependent regulation of the RLR antiviral pathway.