USP4 specifically interacts with tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and TRAF6 but not TRAF3. It deubiquitinates both TRAF2 and TRAF6 in vivo and in vitro, negatively regulating TNFalpha and IL-1beta-induced NF-kappaB activation and cancer cell migration (Xiao et al. 2012). USP25, a negative regulator of the virus-triggered type I IFN signaling pathway, cleaves lysine 48- and lysine 63-linked polyubiquitin chains in vitro and in vivo from DDX58 (Retinoic acid-inducible gene I (RIG-I)), TRAF2, and TRAF6 to inhibit RIG-I-like receptor-mediated IFN signaling (Zhong et al. 2013).