Porcine Reproductive and Respiratory Syndrome Virus nsp1α Inhibits NF-κB Activation by Targeting the Linear Ubiquitin Chain Assembly Complex

Zhu

et al. 2017

J Virol

Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause substantial economic losses to the pig industry worldwide. Heparan sulfate (HS) is used by PRRSV for initial attachment to target cells. However, the role of HS in the late phase of PRRSV infection and the mechanism of virus release from host cells remain largely unknown. In this study, we showed that PRRSV infection caused a decrease in HS expression and upregulated heparanase, the only known enzyme capable of degrading HS. We subsequently demonstrated that the NF-B signaling pathway and cathepsin L protease were involved in regulation of PRRSV infectioninduced heparanase. In addition, we found that ablation of heparanase expression using small interfering RNA duplexes increased cell surface expression of HS and suppressed PRRSV replication and release, whereas overexpression of heparanase reduced HS surface expression and enhanced PRRSV replication and release. These data suggest that PRRSV activates NF-B and cathepsin L to upregulate and process heparanase, and then the active heparanase cleaves HS, resulting in viral release. Our findings provide new insight into the molecular mechanism of PRRSV egress from host cells, which might help us to further understand PRRSV pathogenesis.IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) causes great economic losses each year to the pig industry worldwide. The molecular mechanism of PRRSV release from host cells largely remains a mystery. In this study, we demonstrate that PRRSV activates NF-B and cathepsin L to upregulate and process heparanase, and then the active heparanase is released to the extracellular space and exerts enzymatic activity to cleave heparan sulfate, resulting in viral release. Our findings provide new insight into the molecular mechanism of PRRSV egress from host cells, which might help us to further understand PRRSV pathogenesis.KEYWORDS PRRSV, heparan sulfate, heparanase, viral release, porcine reproductive and respiratory syndrome virus P orcine reproductive and respiratory syndrome (PRRS) has become one of the most important diseases of intensive pig production worldwide since its emergence in the late 1980s (1, 2). This disease is characterized by respiratory disease, weight loss, and poor growth performance, as well as by late-term abortions (3). The causative agent, PRRS virus (PRRSV), is a small, enveloped, positive-sense, single-stranded RNA virus of the genus Arterivirus, in the family Arteriviridae within the order Nidovirales (4, 5). The PRRSV genome is approximately 15 kb in length and consists of at least 12 overlapping open reading frames (6, 7). Due to the genetic and antigenic differences, PRRSV can be divided into European genotype 1 and North American genotype 2, with Lelystad and VR-2332 as prototypical strains, respectively, which share about 60% nucleotide sequence identity (8). In 2006, highly pathogenic PRRSV (HP-PRRSV)

Section: Discussionmentioning

confidence: 85%

Heparanase Upregulation Contributes to Porcine Reproductive and Respiratory Syndrome Virus Release

Zhu

et al. 2017

J Virol

“…Furthermore, recent research showed that the protein encoded by ORF61 in SVV and VZV prevents ubiquitination and degradation of IκBα, thereby suppressing NF-κB-mediated immune responses [65]. Moreover, Jing et al reported that reproductive and respiratory syndrome virus (PRRSV) nsp1α inhibits NF-κB activation by targeting the linear ubiquitin chain assembly complex [66]. It resulted in the reduction of the linear ubiquitin chain assembly complex dependent linear ubiquitination of NF-κB essential modulator (NEMO), revealing an additional mechanism of immune modulation by PRRSV [66].…”

Section: Viral Immune Evasionmentioning

confidence: 99%

“…Moreover, Jing et al reported that reproductive and respiratory syndrome virus (PRRSV) nsp1α inhibits NF-κB activation by targeting the linear ubiquitin chain assembly complex [66]. It resulted in the reduction of the linear ubiquitin chain assembly complex dependent linear ubiquitination of NF-κB essential modulator (NEMO), revealing an additional mechanism of immune modulation by PRRSV [66]. Additionally, some viruses such as HSV and cytomegalovirus have evolved mechanisms that inhibit necroptosis to overcome host antiviral defences.…”

Section: Viral Immune Evasionmentioning

confidence: 99%

Pleiotropic roles of the ubiquitin-proteasome system during viral propagation

Tang

Chen

et al. 2018

Life Sciences

Protein ubiquitination is a highly conserved post-translational modification affecting various biological processes including viral propagation. Ubiquitination has multiple effects on viral propagation, including viral genome uncoating, viral replication, and immune evasion. Ubiquitination of viral proteins is triggered by the ubiquitin-proteasome system (UPS). This involves the covalent attachment of the highly conserved 76 amino acid residue ubiquitin protein to target proteins by the consecutive actions of E1, E2 and E3 enzymes, and the 26S proteasome that together form a multiprotein complex that degrades target proteins. The UPS is the primary cytosolic proteolytic machinery for the selective degradation of various forms of proteins including viral proteins, thereby limiting viral growth in host cells. To combat this host anti-viral machinery, viruses have evolved the ability to employ or subvert the UPS to inactivate or degrade cellular proteins to favour viral propagation. This review highlights our current knowledge on the different roles of the UPS during viral propagation.

“…For example, Du et al (18) reported that the highly pathogenic porcine reproductive and respiratory syndrome virus Nsp1␣ replicating protein can target swine leukocyte antigen class I molecules for proteasomal degradation. Jing et al (19) found that LUBAC-induced NF-B and proinflammatory cytokine expression can be inhibited in the early phase of PRRSV infection. Mechanistically, Nsp1␣ binds to HOIP and HOIL-1L and impairs the interaction between HOIP and SHARPIN, thus reducing the LUBAC-dependent linear ubiquitination of NEMO.…”

mentioning

confidence: 99%

The Superimposed Deubiquitination Effect of OTULIN and Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) Nsp11 Promotes Multiplication of PRRSV

Shi

Zhang

et al. 2018

J Virol

Linear ubiquitination plays an important role in the regulation of the immune response by regulating nuclear factor κB (NF-κB). The linear ubiquitination-specific deubiquitinase ovarian tumor domain deubiquitinase with linear linkage specificity (OTULIN) can control the immune signaling transduction pathway by restricting the Met1-linked ubiquitination process. In our study, the porcine OTLLIN gene was cloned and deubiquitin functions were detected in a porcine reproductive and respiratory syndrome virus (PRRSV)-infected-cell model. PRRSV infection promotes the expression of the OTULIN gene; in turn, overexpression of OTULIN contributes to PRRSV proliferation. There is negative regulation of innate immunity with OTULIN during viral infection. The cooperative effects of swine OTULIN and PRRSV Nsp11 potentiate the ability to reduce levels of cellular protein ubiquitin associated with innate immunity. Importantly, PRRSV Nsp11 recruits OTULIN through a nonenzymatic combination to enhance its ability to remove linear ubiquitination targeting NEMO, resulting in a superimposed effect that inhibits the production of type I interferons (IFNs). Our report presents a new model of virus utilization of the ubiquitin-protease system from the perspective of the viral proteins that interact with cell deubiquitination enzymes, providing new ideas for prevention and control of PRRSV. Deubiquitination effects of swine OTULIN were identified. The interaction between porcine OTULIN and PRRSV Nsp11 is dependent on the OTU domain. PRRSV Nsp11 recruits OTULIN through a nonenzymatic combination to promote removal of linear ubiquitination targeting NEMO, resulting in a superimposed effect that inhibits the production of type I IFNs.