RIG-I contains a C-terminal DExD/H box helicase domain, which is required for ligand recognition, and two N-terminal CARD domains. Upon ligand binding, the CARD domains of RIG-I associate with the CARD domain of the MAVS (also termed IPS-1, VISA, Cardif) adaptor protein, which subsequently translocates to and inserts in the outer mitochondrial membrane via its C-terminal transmembrane domain [17]–[20]. Signaling downstream of MAVS requires the action of various ubiquitin modifying enzymes, which both positively and negatively regulate RIG-I mediated signal transduction [21]. K63-specific ubiquitin ligases (E3s), such as TRIM25 [22] and Riplet [23], [24], have been shown to directly promote RIG-I activation. In addition, well characterized ubiquitin ligases such as TRAF6 [25], [26] and TRAF3 [27] mediate respectively NF-κB and IRF3 activation upon RIG-I stimulation. On the other hand, deubiquitinating enzymes (DUBs), such as DUBA [28], CYLD [29], [30] and OTUB1/2 [31] have been shown to negatively regulate RLR signaling by specifically removing K63-linked polyubiquitin chains from several signaling molecules. Furthermore, various K48-specific ubiquitin ligases, such as AIP4 [32] and TRIAD3A [33] mark respectively MAVS and TRAF3 for proteasome mediated degradation, thus inhibiting further downstream signaling. Additionally, the attachment of K48-specific polyubiquitin chains to the IRF3 and IRF7 transcription factors by E3s such as RAUL [34], TRIM21 [35] and RBCK1 [36] further dampens antiviral signal transduction.