About: Arterivirus nsp4 Antagonizes Interferon Beta Production by Proteolytically Cleaving NEMO at Multiple Sites

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An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Arterivirus nsp4 Antagonizes Interferon Beta Production by Proteolytically Cleaving NEMO at Multiple Sites
Creator	Fang, Liurong Wang, Dang Xiao, Shaobo Gao, Li Zhu, Xinyu Li, Kui Chen, Jiyao Guo, Jiahui Sun, Zheng Xu, Shangen
Source	Medline; PMC
abstract	Equine arteritis virus (EAV) and porcine reproductive and respiratory syndrome virus (PRRSV) represent two members of the family Arteriviridae and pose major threats for the horse- and swine-breeding industries worldwide. A previous study suggested that PRRSV nsp4, a 3C-like protease, antagonizes interferon beta (IFN-β) production by cleaving the NF-κB essential modulator (NEMO) at a single site, glutamate 349 (E349). Here, we demonstrated that EAV nsp4 also inhibited virus-induced IFN-β production by targeting NEMO for proteolytic cleavage and that the scission occurred at four sites: E166, E171, glutamine 205 (Q205), and E349. Additionally, we found that, besides the previously reported cleavage site E349 in NEMO, scission by PRRSV nsp4 took place at two additional sites, E166 and E171. These results imply that while cleaving NEMO is a common strategy utilized by EAV and PRRSV nsp4 to antagonize IFN induction, EAV nsp4 adopts a more complex substrate recognition mechanism to target NEMO. By analyzing the abilities of the eight different NEMO fragments resulting from EAV or PRRSV nsp4 scission to induce IFN-β production, we serendipitously found that a NEMO fragment (residues 1 to 349) could activate IFN-β transcription more robustly than full-length NEMO, whereas all other NEMO cleavage products were abrogated for the IFN-β-inducing capacity. Thus, NEMO cleavage at E349 alone may not be sufficient to completely inactivate the IFN response via this signaling adaptor. Altogether, our findings suggest that EAV and PRRSV nsp4 cleave NEMO at multiple sites and that this strategy is critical for disarming the innate immune response for viral survival. IMPORTANCE The arterivirus nsp4-encoded 3C-like protease (3CL(pro)) plays an important role in virus replication and immune evasion, making it an attractive target for antiviral therapeutics. Previous work suggested that PRRSV nsp4 suppresses type I IFN production by cleaving NEMO at a single site. In contrast, the present study demonstrates that both EAV and PRRSV nsp4 cleave NEMO at multiple sites and that this strategy is essential for disruption of type I IFN production. Moreover, we reveal that EAV nsp4 also cleaves NEMO at glutamine 205 (Q205), which is not targeted by PRRSV nsp4. Notably, targeting a glutamine in NEMO for cleavage has been observed only with picornavirus 3C proteases (3C(pro)) and coronavirus 3CL(pro). In aggregate, our work expands knowledge of the innate immune evasion mechanisms associated with NEMO cleavage by arterivirus nsp4 and describes a novel substrate recognition characteristic of EAV nsp4.
has issue date	2019-04-03(xsd:dateTime)
bibo:doi	10.1128/jvi.00385-19
bibo:pmid	30944180
has license	bronze-oa
sha1sum (hex)	db69147a86435a1d729a28b25d7df41d8be97c42
schema:url	https://doi.org/10.1128/jvi.00385-19
resource representing a document's title	Arterivirus nsp4 Antagonizes Interferon Beta Production by Proteolytically Cleaving NEMO at Multiple Sites
has PubMed Central identifier	PMC6613749
has PubMed identifier	30944180
schema:publication	Journal of Virology
resource representing a document's body	covid:db69147a86435a1d729a28b25d7df41d8be97c42#body_text
is schema:about of	named entity 'NEMO' named entity 'NEMO' named entity 'NEMO' named entity 'induction' named entity 'cleavage' named entity 'Production' named entity 'HERE' named entity 'VIRUS' named entity 'SIGNALING' named entity 'inhibited' named entity 'site' named entity 'IFN' named entity 'critical' named entity 'targeting' named entity 'family' named entity 'additional' named entity 'protease' named entity 'strategy' named entity 'glutamate' named entity 'EAV' named entity 'IFN' named entity 'IFN' named entity 'NF-B' named entity 'IFN' named entity 'E171' named entity 'swine' named entity 'VIRUS-CELL INTERACTIONS' named entity 'Arterivirus' named entity 'NF-B' named entity 'monoclonal antibody' named entity 'signaling protein' named entity 'Arteriviridae' named entity 'Nidovirales' named entity 'IFN' named entity 'hemagglutinin' named entity 'substrates' named entity 'coiled-coil' named entity 'wild-type' named entity 'evolutionary relationship' named entity 'arterivirus' named entity 'Japan' named entity 'respiratory distress' named entity 'MDA5' named entity 'genome' named entity 'ORF' named entity 'viral RNA' named entity 'protease' named entity 'nsp4' named entity 'nsp5' named entity '1, 2' named entity 'alveolar' named entity 'signal molecules' named entity 'China' named entity 'TRIzol' named entity 'Chinese Academy of Agricultural Sciences' named entity 'N-terminal' named entity 'arterivirus' named entity 'avian myeloblastosis virus' named entity 'proteolytic activities' named entity 'RIG-I-like receptor' named entity 'arterivirus' named entity 'arterivirus' named entity 'IPS-1' named entity 'Cardif' named entity 'fluorogenic' named entity 'His-tagged' named entity 'Plasmids' named entity 'TBK1' named entity 'proteases' named entity 'coronavirus' named entity 'C-terminal' named entity 'chymotrypsin'

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