The EMCV protein 2B* is required for efficient cell lysis via both caspase-3-dependent and -independent pathways during infection.

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dc.creatorNguyen, Samantha K
dc.creatorLong, Edward
dc.creatorEdgar, James R
dc.creatorFirth, Andrew E
dc.creatorStewart, Hazel
dc.date2025-01-29T00:30:48Z
dc.date2025-02
dc.date.accessioned2026-08-03T04:09:33Z
dc.description2B* is a poorly characterized protein encoded by an overlapping ORF in the genome of encephalomyocarditis virus (EMCV). We have previously found 2B* to have a role in innate immune antagonism; however, this role is distinct from an earlier described phenotype whereby 2B*KO viruses exhibit extremely small plaques compared to WT. Here, we report that the small plaque phenotype is recapitulated by novel EMCV mutant viruses harbouring mutations across the C-terminal domain of 2B*, confirming a functional role of 2B* in promoting viral spread. We found that 2B*KO EMCV displays impaired extracellular virus titres compared to WT EMCV, despite producing a similar number of infectious particles overall. This correlates with a reduction in cell lysis and lower levels of caspase-3 cleavage occurring during infection. Further investigation using caspase inhibitors and knockout cells revealed that WT EMCV can utilize both caspase-3-dependent and caspase-3-independent pathways to achieve cell lysis, the former of which is likely to be GSDME-mediated pyroptosis. 2B* increases the efficiency of both lytic pathways through an as-yet-undefined mechanism. This work reveals 2B*, a protein only found in EMCV, to be a key regulator of multiple lytic cell death pathways, leading to enhanced rates of virus release. This explains the rapid cell death observed during WT EMCV infection and the small plaque phenotype seen in both 2B*KO and previously described 2B* mutant viruses.
dc.descriptionWellcome Trust Senior Research Fellowships (106207/Z/14/Z, 220814/Z/20/Z) Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (216370/Z/19/Z) Department of Pathology, University of Cambridge PhD studentship funded by the Waldmann Fund
dc.formatapplication/pdf
dc.identifier0022-1317
dc.identifierhttps://www.repository.cam.ac.uk/handle/1810/379389
dc.identifierhttps://doi.org/10.17863/CAM.115497
dc.identifier1465-2099
dc.identifier.urihttps://repo.dare.co.zw/handle/123456789/185701
dc.languageeng
dc.publisherMicrobiology Society
dc.publisherDepartment of Pathology
dc.publisherhttps://doi.org/10.1099/jgv.0.002075
dc.rightsAttribution 4.0 International
dc.rightshttps://creativecommons.org/licenses/by/4.0/
dc.subjectapoptosis
dc.subjectcaspase-3
dc.subjectcell death
dc.subjectencephalomyocarditis virus
dc.subjectpicornavirus
dc.subjectpyroptosis
dc.subjectCaspase 3
dc.subjectHumans
dc.subjectEncephalomyocarditis virus
dc.subjectAnimals
dc.subjectViral Nonstructural Proteins
dc.subjectCell Line
dc.subjectVirus Replication
dc.subjectCardiovirus Infections
dc.titleThe EMCV protein 2B* is required for efficient cell lysis via both caspase-3-dependent and -independent pathways during infection.
dc.typeArticle

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