The Membrane Protein of Severe Acute Respiratory Syndrome Coronavirus Functions as a Novel Cytosolic Pathogen-Associated Molecular Pattern To Promote Beta Interferon Induction via a Toll-Like-Receptor-Related TRAF3-Independent Mechanism

Wang, Yi; Liu, Li

Pathogen-derived proteins such as virus-encoded proteins are frequently documented as negative regulators in subverting type I interferon (IFN-I) induction by interfering with a certain key component(s) of IFN-I activation signaling cascades. Viral evolution may develop a unique strategy to inhibit host innate immunity by generating virus-derived antagonists to some key signaling molecules. The vaccinia virus encodes two Toll/interleukin-1 (IL-1) receptor (TIR) domains containing proteins A46R and A52R, which can negatively regulate TLR signaling by two distinct mechanisms (13) . The vaccinia virus A46R inhibits TLR signaling by physically interacting with the BB loop of TIR containing adaptor proteins such as MyD88 adaptor-like (MAL) and TRIF-related adaptor molecule (TRAM) to disrupt receptor-adaptor (e.g., TLR4-MAL and TLR4-TRAM) interactions (14, 15) . Differently, the A52R protein may function as a dominant negative MyD88 to directly interact with TRAF6 and IRAK2 (16, 17) . On the other hand, the vaccinia virus N1L protein, another protein homologous to A52R, employs a different anti-IFN-I strategy by targeting both the TBK1/IB kinase (IKK) and IKK␣/IKK␤ complexes to inhibit IRF3 and NF-B signaling, respectively (18) . Alternatively, virus may invade the cells to target the retinoic acid-inducible gene I (RIG-I)-like receptor signaling pathways for the prevention of IFN-I induction. For example, the influenza virus nonstructural protein NS1 can sequester either the dsRNA or 5=triphosphate RNA products of viral infection which can be sensed by or directly bound to the RNA helicase sensor RIG-I to inhibit RIG-I-mediated IFN-␤ production (8, 19, 20) . The paramyxovirus V protein inhibits IFN-␤ induction through the blockage of MDA5, another RIG-I-homologous cytosolic dsRNA sensor (21) . A recent study revealed that the transcriptional factor IRF3 might be alternatively targeted and inhibited by the paramyxovirus V protein to impede IFN-␤ gene transcription (22) .