Nonstructural protein 1α subunit-based inhibition of NF-κB activation and suppression of interferon-β production by porcine reproductive and respiratory syndrome virus

Induction of type I interferon (IFN-alpha/beta) is an early antiviral response of the host, and porcine reproductive and respiratory syndrome virus (PRRSV) has been reported to downregulate the IFN response during infection in cells and pigs. We report that the PRRSV nonstructural protein 1 alpha (Nsp1 alpha) subunit of Nsp1 is a nuclear-cytoplasmic protein distributed to the nucleus and contains a strong suppressive activity for IFN-beta production that is mediated through the retinoic acid-inducible gene I (RIG-I) signaling pathway. Nsp1 alpha suppressed the activation of nuclear factor (NF)-kappa B when stimulated with dsRNA or tumor necrosis factor (TNF)-alpha, and NF-kappa B suppression was RIG-I-dependent. The suppression of NF-kappa B activation was associated with the poor production of IFN-beta during PRRSV infection. The C-terminal 14 amino acids of the Nsp1 alpha subunit were critical in maintaining immunosuppressive activity of Nsp1 alpha for both IFN-beta and NF-kappa B, suggesting that the newly identified zinc finger configuration comprising of Met180 may be crucial for inhibitory activities. Nsp1 alpha inhibited I kappa B phosphorylation and as a consequence NF-kappa B translocation to the nucleus was blocked, leading to the inhibition of NF-kappa B stimulated gene expression. Our results suggest that PRRSV Nsp1 alpha is a multifunctional nuclear protein participating in the modulation of the host IFN system. (C) 2010 Elsevier Inc. All rights reserved.