RESUMEN
The multifunctional V protein of human parainfluenza virus type 2 (hPIV2) plays important roles in controlling viral genome replication, inhibiting the host interferon response and promoting virus growth. We screened a yeast two-hybrid library using V protein as bait to identify host factors that are important for other functions of V. One of several positive clones isolated from HeLa cell-derived cDNA library encodes caspase-1. We found that the C-terminal region of V interacts with the C-terminal region of caspase-1 in mammalian cells. Moreover, the V protein repressed caspase-1 activity and the formation of interleukin-1ß (IL-1ß) in a dose-dependent manner. IL-1ß secretion induced by wild-type hPIV2 infection in human monocytic THP-1 cells was significantly lower than that induced by recombinant hPIV2 lacking V protein or having a mutant V. These data suggest that hPIV2 V protein inhibits caspase-1-mediated maturation of IL-1ß via its interaction with caspase-1.
Asunto(s)
Caspasa 1/metabolismo , Virus de la Parainfluenza 2 Humana/metabolismo , Infecciones por Rubulavirus/enzimología , Proteínas Virales/metabolismo , Secuencias de Aminoácidos , Caspasa 1/química , Caspasa 1/genética , Células HeLa , Interacciones Huésped-Patógeno , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Virus de la Parainfluenza 2 Humana/química , Virus de la Parainfluenza 2 Humana/genética , Unión Proteica , Infecciones por Rubulavirus/genética , Infecciones por Rubulavirus/virología , Proteínas Virales/química , Proteínas Virales/genética , Replicación ViralRESUMEN
RIG-I and mda-5 are activated by viral RNA and stimulate type I interferon production. Laboratory of genetics and physiology 2 (LGP2) shares homology with RIG-I and mda-5 but lacks the CARD domains required for signaling. The V proteins of paramyxoviruses limit interferon induction by binding mda-5 and preventing its activation; however, they do not bind RIG-I and have not been considered inhibitors of RIG-I signaling. Here we uncover a novel mechanism of RIG-I inhibition in which the V protein of parainfluenzavirus type 5 (PIV5; formerly known as simian virus type 5 [SV5]) interacts with LGP2 and cooperatively inhibits induction by RIG-I ligands. A complex between RIG-I and LGP2 is observed in the presence of PIV5-V, and we propose that this complex is refractory to activation by RIG-I ligands. The V proteins from other paramyxoviruses also bind LGP2 and demonstrate LGP2-dependent inhibition of RIG-I signaling. This is significant, because it demonstrates a general mechanism for the targeting of the RIG-I pathway by paramyxoviruses.
