Degradation of CREB-binding protein and modulation of type I interferon induction by the zinc finger motif of the porcine reproductive and respiratory syndrome virus nsp1 alpha subunit

作者：Han Mingyuan; Du Yijun; Song Cheng; Yoo Dongwan^*

来源：Virus Research, 2013, 172(1-2): 54-65.

DOI：10.1016/j.virusres.2012.12.012

• Arterivirus
• Nidovirus
• Immune evasion
• Interferon modulation
• Non-structural protein
• PRRS
• nsp1
• CREB binding protein
• CBP
• PML
• Zinc finger
• Interferon antagonist

Non-structural protein (nsp) 1 of PRRS virus is a viral antagonist for type I interferons (IFNs), and in cells expressing nsp1, CREB-binding protein (CBP) is degraded. nsp1 is auto-processed into nsp1 alpha and nsp1 beta subunits and in the present study we show that the nsp1 alpha subunit was responsible for CBP degradation. The nsp1 alpha subunit contains three distinct functional motifs; a papain-like cysteine protease alpha (PCP alpha) motif, an N-terminal zinc finger motif (ZF1), and a newly reported C-terminal zinc finger motif (ZF2). To study the structure function of nsp1 alpha and its IFN antagonism, these motifs were individually mutated and the mutants were examined for their IFN suppression ability. The mutations that destroyed the PCPa activities (C76S, H146Y, and C76S/H146Y) did not affect the IFN suppressive activity of nsp1 alpha, indicating that the cysteine protease activity did not participate in IFN suppression. The mutations of C70S, C76S, H146Y, and/or M180I which coordinated the ZF2 motif also did not alter IFN suppression. However, the mutations of C8S, Cl OS, C25S, and/or C28S for the ZF1 motif impaired the IFN antagonism of nsp1 alpha, demonstrating that ZF1 was the essential element of nsp1 alpha for IFN suppression. Wild-type nsp1 alpha localized in the both nucleus and cytoplasm, but the ZF1 mutants that lost the IFN suppressive activity did not localize in the nucleus and remained in the cytoplasm. Consistent with their cytoplasmic distribution, CBP was not degraded by these mutants. Our results indicate that the ZF1 motif of nsp1 alpha plays an important role for IFN regulation and further demonstrate that the CBP degradation is likely the key mechanism for IFN suppression mediated by the nsp1 alpha subunit protein of PRRS virus.

• 出版日期2013-3