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bioRxiv · 10.1101/2023.08.04.552021

Nonstructural protein 1 of swine arterivirus PRRSV downregulates promyelocytic leukemia nuclear bodies and promotes viral replication

Su, C.-M.·Han, M.·Everett, R. D.·Yoo, D.
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Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) inhibits the type I interferon (IFN) production and signaling pathways during infection, and the nonstructural protein 1 (nsp1) has been identified as a potent IFN antagonist. Promyelocytic leukemia (PML) protein is a major scaffold protein organizing the PML nuclear bodies (NBs) of the cell and plays a diverse role in maintaining the cellular homeostasis including antiviral response among many other processes. The present study reveals a significant reduction of PML NBs in cells during infection of PRRSV, implicating the negative regulation of PML gene expression by PRRSV. Subsequently, the nsp1{beta} protein was identified as the viral regulator for PML expression. The overexpression of PML isoforms restricted viral replication, while the gene silencing of endogenous PML promoted viral replication. The downregulation of PML expression by PRRSV was post-translational via the ubiquitination-proteasome pathway. Of six isoforms, PML-II and PML-IV exhibited the most potent suppressive activity against viral replication. PRRSV nsp1{beta} bound to PML directly, and this interaction was mediated through the small ubiquitin-like modifier (SUMO)-interacting motifs (SIMs) on nsp1{beta}. Further studies revealed that double mutations in SIM1 and SIM4 abolished the binding of nsp1{beta} to PML and prevented the PML degradation. The PML downregulation by nsp1 was common in other arteriviruses including equine arteritis virus, murine lactate dehydrogenase elevating virus, and simian hemorrhagic fever virus. Our study unveils the evolutionary conservation of the viral immune evasion strategy employed by arteriviruses, which promotes their replication by targeting PML for downregulation. IMPORTANCE OF THE STUDYPorcine reproductive and respiratory syndrome (PRRS) is an economically significant disease in the swine industry worldwide. One of the immunological hallmarks in virus-infected animals is the suppression of type I interferon response during an early-stage infection, leading to the consequence of adaptive immunity and viral persistence. In the present study, we report that the nsp1-beta protein of PRRS virus degrades the promyelocytic leukemia (PML) protein and downregulates PML nuclear body (NB) formation. The PML downregulation by PRRS virus results in enhanced viral replication. The PML downregulation by nsp1 is common in other arteriviruses, unveiling the basic understanding of cell-virus interactions and immune evasion strategies for arteriviruses.

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Su, C.-M., Han, M., Everett, R. D., Yoo, D.. 2023-08-04. Nonstructural protein 1 of swine arterivirus PRRSV downregulates promyelocytic leukemia nuclear bodies and promotes viral replication. https://doi.org/10.1101/2023.08.04.552021

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