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Their large genomes encode for over 200 proteins and many of these help establish infection by inhibiting cell death or interfering with host antiviral signalling pathways. This includes the poxviral B cell lymphoma-2 (Bcl-2) proteins, which are found in most of the Chordopoxvirinae (vertebrate-infecting poxviruses), with individual viruses possessing multiple Bcl-2 proteins. These proteins are so named for the fact that they adopt an alpha helical bundle with structural similarity to cellular anti-apoptotic Bcl-2 proteins, despite lacking obvious primary amino acid sequence identity with these proteins. Not surprisingly, initial studies found that some poxviral Bcl-2 proteins inhibit apoptosis; however, it was soon clear that these proteins have additional functions. This brief review highlights some of these other activities that have either been more recently identified or for which additional mechanistic insight has been acquired. This includes the role of poxviral Bcl-2 proteins in modulating nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein (NLRP) inflammasome activation and inhibiting antiviral signalling regulated by the interferon regulatory factor 3 and 7 (IRF3\/7) transcription factors. Finally, we discuss how poxviral Bcl-2 proteins interfere with cellular antiviral TRIM family E3 ubiquitin-ligases to promote virus replication.<\/jats:p>","DOI":"10.1042\/bst20250100","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T10:56:12Z","timestamp":1770375372000},"page":"155-166","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Poxviral Bcl-2 proteins: multifunctional manipulators of the host cell"],"prefix":"10.1042","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5063-9742","authenticated-orcid":false,"given":"Summer","family":"Smyth","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, and Striving for Pandemic Preparedness \u2013 The Alberta Research Consortium (SPP-ARC), 6-020 Katz Group Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, T6G 2E1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8595-7594","authenticated-orcid":false,"given":"Jianing","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, and Striving for Pandemic Preparedness \u2013 The Alberta Research Consortium (SPP-ARC), 6-020 Katz Group Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, T6G 2E1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7002-0264","authenticated-orcid":false,"given":"Grace","family":"Melvie","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, and Striving for Pandemic Preparedness \u2013 The Alberta Research Consortium (SPP-ARC), 6-020 Katz Group Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, T6G 2E1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2482-8641","authenticated-orcid":false,"given":"Robert\u00a0J.","family":"Ingham","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, and Striving for Pandemic Preparedness \u2013 The Alberta Research Consortium (SPP-ARC), 6-020 Katz Group Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, T6G 2E1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"2026040112221895000_B1","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.clindermatol.2005.11.009","article-title":"The history of smallpox","volume":"24","author":"Geddes","year":"2006","journal-title":"Clin. 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