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

ABSTRACT 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.