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Interaction of PIAS1 with PRRS virus nucleocapsid protein mediates NF-?B activation and triggers proinflammatory mediators during viral infection.

ABSTRACT: Porcine reproductive and respiratory syndrome virus (PRRSV) activates NF-?B during infection. We examined the ability of all 22 PRRSV genes for NF-?B regulation and determined the nucleocapsid (N) protein as the NF-?B activator. Protein inhibitor of activated STAT1 (signal transducer and activator of transcription 1) (PIAS1) was identified as a cellular protein binding to N. PIAS1 is known to bind to p65 (RelA) in the nucleus and blocks its DNA binding, thus functions as a repressor of NF-?B. Binding of N to PIAS1 released p65 for NF-?B activation. The N-terminal half of PIAS1 was mapped as the N-binding domain, and this region overlapped its p65-binding domain. For N, the region between 37 and 72 aa was identified as the binding domain to PIAS1, and this domain alone was able to activate NF-?B. A nuclear localization signal (NLS) knock-out mutant N did not activate NF-?B, and this is mostly likely due to the lack of its interaction with PIAS1 in the nucleus, demonstrating the positive correlation between the binding of N to PIAS1 and the NF-?B activation. Our study reveals a role of N in the nucleus for NF-?B activation and proinflammatory cytokine production during infection.

SUBMITTER: Ke H

PROVIDER: S-EPMC6667501 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Interaction of PIAS1 with PRRS virus nucleocapsid protein mediates NF-κB activation and triggers proinflammatory mediators during viral infection.

Ke Hanzhong H Lee Sera S Kim Jineui J Liu Hsiao-Ching HC Yoo Dongwan D

Scientific reports 20190730 1

Porcine reproductive and respiratory syndrome virus (PRRSV) activates NF-κB during infection. We examined the ability of all 22 PRRSV genes for NF-κB regulation and determined the nucleocapsid (N) protein as the NF-κB activator. Protein inhibitor of activated STAT1 (signal transducer and activator of transcription 1) (PIAS1) was identified as a cellular protein binding to N. PIAS1 is known to bind to p65 (RelA) in the nucleus and blocks its DNA binding, thus functions as a repressor of NF-κB. Bi ...[more]

PMID: 31363150

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Project description:The nuclear factor kappa B (NF-κB) pathway is known to integrate signaling associated with very diverse intra- and extracellular stressors, including virus infections, and triggers a powerful (proinflammatory) response through the expression of NF-κB-regulated genes. Typically, the NF-κB pathway collects and transduces threatening signals at the cell surface or in the cytoplasm leading to nuclear import of activated NF-κB transcription factors. In the current work, we demonstrate that the swine alphaherpesvirus pseudorabies virus (PRV) induces a peculiar mode of NF-κB activation known as "inside-out" NF-κB activation. We show that PRV triggers the DNA damage response (DDR) and that this DDR response drives NF-κB activation since inhibition of the nuclear ataxia telangiectasia-mutated (ATM) kinase, a chief controller of DDR, abolished PRV-induced NF-κB activation. Initiation of the DDR-NF-κB signaling axis requires viral protein synthesis but occurs before active viral genome replication. In addition, the initiation of the DDR-NF-κB signaling axis is followed by a virus-induced complete shutoff of NF-κB-dependent gene expression that depends on viral DNA replication. In summary, the results presented in this study reveal that PRV infection triggers a noncanonical DDR-NF-κB activation signaling axis and that the virus actively inhibits the (potentially antiviral) consequences of this pathway, by inhibiting NF-κB-dependent gene expression. IMPORTANCE The NF-κB signaling pathway plays a critical role in coordination of innate immune responses that are of vital importance in the control of infections. The current report generates new insights into the interaction of the alphaherpesvirus pseudorabies virus (PRV) with the NF-κB pathway, as they reveal that (i) PRV infection leads to NF-κB activation via a peculiar "inside-out" nucleus-to-cytoplasm signal that is triggered via the DNA damage response (DDR), (ii) the DDR-NF-κB signaling axis requires expression of viral proteins but is initiated before active PRV replication, and (iii) late viral factor(s) allow PRV to actively and efficiently inhibit NF-κB-dependent (proinflammatory) gene expression. These data suggest that activation of the DDR-NF-κB during PRV infection is host driven and that its potential antiviral consequences are actively inhibited by the virus.

Dataset Information

Interaction of PIAS1 with PRRS virus nucleocapsid protein mediates NF-?B activation and triggers proinflammatory mediators during viral infection.

Publications

Interaction of PIAS1 with PRRS virus nucleocapsid protein mediates NF-κB activation and triggers proinflammatory mediators during viral infection.

Similar Datasets

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