Biogenesis of non-structural protein 1 (nsp1) and nsp1-mediated type I interferon modulation in arteriviruses

Type I interferons (IFNs-alpha/beta) play a key role for the antiviral state of host, and the porcine arterivirus; porcine reproductive and respiratory syndrome virus (PRRSV), has been shown to down-regulate the production of IFNs during infection. Non-structural protein (nsp) 1 of PRRSV has been identified as a viral IFN antagonist, and the nsp1 alpha subunit of nsp1 has been shown to degrade the CREB-binding protein (CBP) and to inhibit the formation of enhanceosome thus resulting in the suppression of IFN production. The study was expanded to other member viruses in the family Arteriviridae: equine arteritis virus (EAV), murine lactate dehydrogenase-elevating virus (LDV), and simian hemorrhagic fever virus (SHFV). While PRRSV-nsp1 and LDV-nsp1 were auto-cleaved to produce the nsp1 alpha and nsp1 beta subunits, EAV-nsp1 remained uncleaved. SHFV-nsp1 was initially predicted to be cleaved to generate three subunits (nsp1 alpha, nsp1 beta, and nsp1 gamma), but only two subunits were generated as SHFV-nsp1 alpha beta and SHFV-nsp1 gamma. The papain-like cysteine protease (PLP) lot motif in nsp1 alpha remained inactive for SHFV, and only the PLP1 beta motif of nsp1 beta was functional to generate SHFV-nsp1 gamma subunit. All subunits of arterivirus nsp1 were localized in the both nucleus and cytoplasm, but PRRSV-nsp1 beta p, LDV-nsp1 beta, EAV-nsp1, and SHFV-nsp1 gamma were predominantly found in the nucleus. All subunits of arterivirus nsp1 contained the IFN suppressive activity and inhibited both interferon regulatory factor 3 (IRF3) and NF-kappa B mediated IFN promoter activities. Similar to PRRSV-nsp1 alpha, CBP degradation was evident in cells expressing LDV-nsp1 alpha and SHFV-nsp1 gamma, but no such degradation was observed for EAV-nsp1. Regardless of CBP degradation, all subunits of arterivirus nsp1 suppressed the IFN-sensitive response element (ISRE)promoter activities. Our data show that the nsp1-mediated IFN modulation is a common strategy for all arteriviruses but their mechanism of action may differ from each other. (C) 2014 Elsevier Inc. All rights reserved.