Firstly, RNF115 constitutively catalyzed K48-linked ubiquitination on Lys500 of MAVS, and VSV infection or transfection of poly(I:C) disrupted RNF115–MAVS associations, which frees the Lys500 residue that is modified with K63-linked ubiquitination after viral infection in an unknown mechanism for subsequent recruitment and activation of IKKε59. Here, RNF115 is linked to viral infectious disease.