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Seneca Valley Virus Induces DHX30 Cleavage to Antagonize Its Antiviral Effects.

ABSTRACT: Seneca Valley virus (SVV) is a new pathogen associated with porcine idiopathic vesicular disease (PIVD) in recent years. However, SVV-host interaction is still unclear. In this study, through LC-MS/MS analysis and coimmunoprecipitation analysis, DHX30 was identified as a 3C^pro-interacting protein. 3C^pro mediated the cleavage of DHX30 at a specific site, which depends on its protease activity. Further study showed that DHX30 was an intrinsic antiviral factor against SVV that was dependent on its helicase activity. DHX30 functioned as a viral-RNA binding protein that inhibited SVV replication at the early stage of viral infection. RIP-seq showed comparatively higher coverage depth at SVV 5'UTR, but the distribution across SVV RNA suggested that the interaction had low specificity. DHX30 expression strongly inhibited double-stranded RNA (dsRNA) production. Interestingly, DHX30 was determined to interact with 3D in an SVV RNA-dependent manner. Thus, DHX30 negatively regulated SVV propagation by blocking viral RNA synthesis, presumably by participating in the viral replication complex. IMPORTANCE DHX30, an RNA helicase, is identified as a 3C^pro-interacting protein regulating Seneca Valley virus (SVV) replication dependent on its helicase activity. DHX30 functioned as a viral-RNA binding protein that inhibited SVV replication at the early stage of virus infection. DHX30 expression strongly inhibited double-stranded RNA (dsRNA) production. In addition, 3C^pro abolished DHX30 antiviral effects by inducing DHX30 cleavage. Thus, DHX30 is an intrinsic antiviral factor that inhibits SVV replication.

SUBMITTER: Wen W

PROVIDER: S-EPMC9472649 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Seneca Valley Virus Induces DHX30 Cleavage to Antagonize Its Antiviral Effects.

Wen Wei W Zheng Zixuan Z Wang Haoyuan H Zhao Qiongqiong Q Yin Mengge M Chen Huanchun H Li Xiangmin X Qian Ping P

Journal of virology 20220824 17

Seneca Valley virus (SVV) is a new pathogen associated with porcine idiopathic vesicular disease (PIVD) in recent years. However, SVV-host interaction is still unclear. In this study, through LC-MS/MS analysis and coimmunoprecipitation analysis, DHX30 was identified as a 3C<sup>pro</sup>-interacting protein. 3C<sup>pro</sup> mediated the cleavage of DHX30 at a specific site, which depends on its protease activity. Further study showed that DHX30 was an intrinsic antiviral factor against SVV that ...[more]

PMID: 36000840

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Project description:Members of the gasdermin (GSDM) family are critical for inducing programmable pyroptosis by forming pores on the cell membrane. GSDMB, GSDMC, GSDMD, and GSDME are activated by caspases or granzyme, leading to the release of their autoinhibitory domains. The protease SpeB from group A Streptococcus has been shown to cleave and activate GSDMA-mediated pyroptosis. Meanwhile, African Swine Fever Virus infection regulates pyroptosis by cleaving porcine GSDMA (pGSDMA) via active caspase-3 and caspase-4. However, it is not known whether virus-encoded proteases also target GSDMA. Here, we show that residues 1-252 of pGSDMA (pGSDMA1-252) is the pore-forming fragment that induces lytic cell death and pyroptosis. Interestingly, Seneca Valley Virus (SVV) infection induces the cleavage of both pGSDMA and human GSDMA and suppresses GSDMA-mediated cell death. Mechanistically, SVV protease 3C cleaves pGSDMA between Q187 and G188 to generate a shorter fragment, pGSDMA1-186, which fails to induce lytic cell death and lactate dehydrogenase release. Furthermore, pGSDMA1-186 does not localize to the plasma membrane and does not induce cell death, thereby promoting viral replication by suppressing host immune responses. These studies reveal a sophisticated evolutionary adaptation of SVV to bypass GSDMA-mediated pyroptosis, allowing it to overcome host inflammatory defenses.ImportanceGasdermin A (GSDMA) remains a protein shrouded in mystery, particularly regarding its regulation by virus-encoded proteases. Previous studies have identified human GSDMA (hGSDMA) as a sensor and substrate of the SpeB from group A Streptococcus, which initiates pyroptosis. However, it is not clear if viral proteases also cleave GSDMA. In this study, we show that a fragment of porcine GSDMA (pGSDMA) containing the first 252 residues constitutes the pore-forming domain responsible for inducing lytic cell death and pyroptosis. Interestingly, picornavirus Seneca Valley Virus (SVV) protease 3C cleaves both pGSDMA and hGSDMA, generating a shorter fragment that fails to associate with the plasma membrane and does not induce pyroptosis. This cleavage by SVV 3C suppresses GSDMA-mediated lactate dehydrogenase release, bactericidal activity, and lytic cell death. This study reveals how SVV subverts host inflammatory defense by disrupting GSDMA-induced pyroptosis, thereby advancing our understanding of antiviral immunity and opening avenues for treating GSDMA-associated autoimmune diseases.

Project description:Seneca Valley virus (SVV) is an oncolytic RNA virus belonging to the Picornaviridae family. Its nucleotide sequence is highly similar to those of members of the Cardiovirus genus. SVV is also a neuroendocrine cancer-selective oncolytic picornavirus that can be used for anticancer therapy. However, the interaction between SVV and its host is yet to be fully characterized. In this study, SVV inhibited antiviral type I interferon (IFN) responses by targeting different host adaptors, including mitochondrial antiviral signaling (MAVS), Toll/interleukin 1 (IL-1) receptor domain-containing adaptor inducing IFN-β (TRIF), and TRAF family member-associated NF-κB activator (TANK), via viral 3C protease (3Cpro). SVV 3Cpro mediated the cleavage of MAVS, TRIF, and TANK at specific sites, which required its protease activity. The cleaved MAVS, TRIF, and TANK lost the ability to regulate pattern recognition receptor (PRR)-mediated IFN production. The cleavage of TANK also facilitated TRAF6-induced NF-κB activation. SVV was also found to be sensitive to IFN-β. Therefore, SVV suppressed antiviral IFN production to escape host antiviral innate immune responses by cleaving host adaptor molecules.IMPORTANCE Host cells have developed various defenses against microbial pathogen infection. The production of IFN is the first line of defense against microbial infection. However, viruses have evolved many strategies to disrupt this host defense. SVV, a member of the Picornavirus genus, is an oncolytic virus that shows potential functions in anticancer therapy. It has been demonstrated that IFN can be used in anticancer therapy for certain tumors. However, the relationship between oncolytic virus and innate immune response in anticancer therapy is still not well known. In this study, we showed that SVV has evolved as an effective mechanism to inhibit host type I IFN production by using its 3Cpro to cleave the molecules MAVS, TRIF, and TANK directly. These molecules are crucial for the Toll-like receptor 3 (TLR3)-mediated and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-mediated signaling pathway. We also found that SVV is sensitive to IFN-β. These findings increase our understanding of the interaction between SVV and host innate immunity.

Dataset Information

Seneca Valley Virus Induces DHX30 Cleavage to Antagonize Its Antiviral Effects.

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Seneca Valley Virus Induces DHX30 Cleavage to Antagonize Its Antiviral Effects.

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