About: Dissecting distinct proteolytic activities of FMDV L(pro) implicates cleavage and degradation of RLR signaling proteins, not its deISGylase/DUB activity, in type I interferon suppression

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About: Dissecting distinct proteolytic activities of FMDV L(pro) implicates cleavage and degradation of RLR signaling proteins, not its deISGylase/DUB activity, in type I interferon suppression Goto Sponge NotDistinct Permalink

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	Dissecting distinct proteolytic activities of FMDV L(pro) implicates cleavage and degradation of RLR signaling proteins, not its deISGylase/DUB activity, in type I interferon suppression
Creator	Langereis, Martijn Visser, Linda Olek, Karin Chiara, Aloise De Groot Id, Raoul De Los Santos, Teresa Id, Tim Komander Id, David Medina 4☯¤, Gisselle Rabouw 1¤, Huib Swatek Id, Van Kuppeveld Id, Frank
Source	Medline; PMC
abstract	The type I interferon response is an important innate antiviral pathway. Recognition of viral RNA by RIG-I-like receptors (RLRs) activates a signaling cascade that leads to type I interferon (IFN-α/β) gene transcription. Multiple proteins in this signaling pathway (e.g. RIG-I, MDA5, MAVS, TBK1, IRF3) are regulated by (de)ubiquitination events. Most viruses have evolved mechanisms to counter this antiviral response. The leader protease (L(pro)) of foot-and-mouth-disease virus (FMDV) has been recognized to reduce IFN-α/β gene transcription; however, the exact mechanism is unknown. The proteolytic activity of L(pro) is vital for releasing itself from the viral polyprotein and for cleaving and degrading specific host cell proteins, such as eIF4G and NF-κB. In addition, L(pro) has been demonstrated to have deubiquitination/deISGylation activity. L(pro)’s deubiquitination/deISGylation activity and the cleavage/degradation of signaling proteins have both been postulated to be important for reduced IFN-α/β gene transcription. Here, we demonstrate that TBK1, the kinase that phosphorylates and activates the transcription factor IRF3, is cleaved by L(pro) in FMDV-infected cells as well as in cells infected with a recombinant EMCV expressing L(pro). In vitro cleavage experiments revealed that L(pro) cleaves TBK1 at residues 692–694. We also observed cleavage of MAVS in HeLa cells infected with EMCV-L(pro), but only observed decreasing levels of MAVS in FMDV-infected porcine LFPK αVβ6 cells. We set out to dissect L(pro)’s ability to cleave RLR signaling proteins from its deubiquitination/deISGylation activity to determine their relative contributions to the reduction of IFN-α/β gene transcription. The introduction of specific mutations, of which several were based on the recently published structure of L(pro) in complex with ISG15, allowed us to identify specific amino acid substitutions that separate the different proteolytic activities of L(pro). Characterization of the effects of these mutations revealed that L(pro)’s ability to cleave RLR signaling proteins but not its deubiquitination/deISGylation activity correlates with the reduced IFN-β gene transcription.
has issue date	2020-07-15(xsd:dateTime)
bibo:doi	10.1371/journal.ppat.1008702
bibo:pmid	32667958
has license	cc0
sha1sum (hex)	71865d9a03817b7762bd47e5b7ab38687438388a
schema:url	https://doi.org/10.1371/journal.ppat.1008702
resource representing a document's title	Dissecting distinct proteolytic activities of FMDV L(pro) implicates cleavage and degradation of RLR signaling proteins, not its deISGylase/DUB activity, in type I interferon suppression
has PubMed Central identifier	PMC7384677
has PubMed identifier	32667958
schema:publication	PLoS Pathog
resource representing a document's body	covid:71865d9a03817b7762bd47e5b7ab38687438388a#body_text
is schema:about of	named entity 'Most' named entity 'evolved' named entity 'pro' named entity 'activates' named entity 'RIG-I' named entity 'IRF3' named entity 'transcription factor' named entity 'receptors' named entity 'vital' named entity 'proteolytic' named entity 'CLEAVAGE' named entity 'CLEAVES' named entity 'SPECIFIC' named entity 'HERE' named entity 'PROTEOLYTIC ACTIVITY' named entity '27S' named entity 'ACTIVITY' named entity 'VIRAL' named entity 'RELEASING' named entity 'PATHWAY' named entity 'VITAL' named entity 'MECHANISM' named entity 'MECHANISMS' named entity 'cells' named entity 'EMCV' named entity 'levels' named entity 'expressing' named entity 'ISG15' named entity 'IFNβ' named entity 'NP-40' named entity 'antibodies' named entity 'gene transcription' named entity 'centrifugation' named entity 'FMDV' named entity 'titrated' named entity 'TBK1' named entity 'SDS-PAGE' named entity 'FMDV' named entity 'MAVS' named entity 'FMDV' named entity 'HeLa' named entity 'eIF4G' named entity 'IFN-β' named entity 'RLR' named entity 'eIF4G' named entity 'FMDV' named entity 'RLR' named entity 'MAVS' named entity 'PLP2' named entity 'TBK1' named entity 'dsRNA' named entity 'papain' named entity 'ubiquitin' named entity 'IFN-α/β' named entity 'transfected' named entity 'extracellular' named entity 'viral proteins' named entity 'TBK1' named entity 'EMCV' named entity 'N-terminal' named entity 'RLR' named entity 'recombinant' named entity 'transcription factors' named entity 'hpi' named entity 'TBK1' named entity 'Nidovirales' named entity 'mRNA' named entity 'cleavage site' named entity 'mutation' named entity 'HEPES'

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