Importantly, RIG-I is activated by E3 ligase tripartite motif protein 25 (TRIM25) via polyubiquitination at K172 residue (Sanchez et al., 2016); MDA5 is proteolytically inactivated by the polyubiquitination mediated by poly (rC) binding protein 2 (PCBP2) with assistance from AIP4/ITCH (Atrophin 1 Interacting Protein 4; also called ITCH) (You et al., 2009).