PA28 modulates antigen processing and viral replication during coxsackievirus B3 infection
The function of the proteasome is modulated at the level of subunit expression and by association with its regulatory complexes. During coxsackievirus B3 (CVB3) myocarditis, IFN-induced formation of immunoproteasomes (ip) is known to be critical for regulating immune modulating molecules. The functi...
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| creator | Respondek, Dorota Voss, Martin Kühlewindt, Ina Klingel, Karin Krüger, Elke Beling, Antje |
| description | The function of the proteasome is modulated at the level of subunit expression and by association with its regulatory complexes. During coxsackievirus B3 (CVB3) myocarditis, IFN-induced formation of immunoproteasomes (ip) is known to be critical for regulating immune modulating molecules. The function of the IFN-γ-inducible proteasome regulator subunits PA28 α and β, however, in this context was unknown. During viral myocarditis, we found an increased abundance of PA28β subunits in heart tissue. PA28α/β exists in PA28-20S-PA28 and PA700-20S-PA28 hybrid proteasome complexes in cells both with either predominant ip and standard proteasome (sp) expression. Being in line with reduced proteasome activity in PA28α/β-deficient cells, we observed increased levels of oxidized and poly-ubiquitinated proteins upon TLR3-activation in these cells. Moreover, PA28α/β is capable to interfere directly with viral replication of CVB3 and facilitates the generation of CVB3-derived MHC class I epitopes by the proteasome. In contrast to a distinct function of PA28α/β in vitro, gene ablation of PA28α/β in mice being on a genetic background with resistance towards the development of severe infection had no significant impact on disease progression. Other than reported for the ip, in this host PA28α/β is dispensable to meet the demand of increased peptide hydrolysis capacity by the proteasome during viral myocarditis. |
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During coxsackievirus B3 (CVB3) myocarditis, IFN-induced formation of immunoproteasomes (ip) is known to be critical for regulating immune modulating molecules. The function of the IFN-γ-inducible proteasome regulator subunits PA28 α and β, however, in this context was unknown. During viral myocarditis, we found an increased abundance of PA28β subunits in heart tissue. PA28α/β exists in PA28-20S-PA28 and PA700-20S-PA28 hybrid proteasome complexes in cells both with either predominant ip and standard proteasome (sp) expression. Being in line with reduced proteasome activity in PA28α/β-deficient cells, we observed increased levels of oxidized and poly-ubiquitinated proteins upon TLR3-activation in these cells. Moreover, PA28α/β is capable to interfere directly with viral replication of CVB3 and facilitates the generation of CVB3-derived MHC class I epitopes by the proteasome. In contrast to a distinct function of PA28α/β in vitro, gene ablation of PA28α/β in mice being on a genetic background with resistance towards the development of severe infection had no significant impact on disease progression. Other than reported for the ip, in this host PA28α/β is dispensable to meet the demand of increased peptide hydrolysis capacity by the proteasome during viral myocarditis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0173259</identifier><identifier>PMID: 28278207</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Antigen Presentation ; Antigen processing ; Antigens ; Autoantigens - immunology ; Biology and Life Sciences ; Cardiomyocytes ; Coxsackievirus infections ; Coxsackievirus Infections - immunology ; Coxsackievirus Infections - metabolism ; Coxsackievirus Infections - virology ; Coxsackieviruses ; Cytokines ; Enterovirus ; Enterovirus B, Human - immunology ; Epitopes ; Female ; Genetic aspects ; Health aspects ; Heart ; Heart diseases ; Homeostasis ; Infections ; Interferon ; Laboratory animals ; Major histocompatibility complex ; Medicine and Health Sciences ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocarditis ; Myocarditis - immunology ; Myocarditis - metabolism ; Myocarditis - virology ; Oxidative stress ; Peptides ; Physiology ; Picornaviridae ; Proteasome Endopeptidase Complex - immunology ; Proteasome Endopeptidase Complex - metabolism ; Proteasome Endopeptidase Complex - physiology ; Proteasomes ; Proteins ; Replication ; Research and analysis methods ; Stem cells ; Studies ; TLR3 protein ; Toll-like receptors ; Ubiquitin-proteasome system ; Virus Replication ; γ-Interferon</subject><ispartof>PloS one, 2017-03, Vol.12 (3), p.e0173259-e0173259</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Respondek et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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During coxsackievirus B3 (CVB3) myocarditis, IFN-induced formation of immunoproteasomes (ip) is known to be critical for regulating immune modulating molecules. The function of the IFN-γ-inducible proteasome regulator subunits PA28 α and β, however, in this context was unknown. During viral myocarditis, we found an increased abundance of PA28β subunits in heart tissue. PA28α/β exists in PA28-20S-PA28 and PA700-20S-PA28 hybrid proteasome complexes in cells both with either predominant ip and standard proteasome (sp) expression. Being in line with reduced proteasome activity in PA28α/β-deficient cells, we observed increased levels of oxidized and poly-ubiquitinated proteins upon TLR3-activation in these cells. Moreover, PA28α/β is capable to interfere directly with viral replication of CVB3 and facilitates the generation of CVB3-derived MHC class I epitopes by the proteasome. In contrast to a distinct function of PA28α/β in vitro, gene ablation of PA28α/β in mice being on a genetic background with resistance towards the development of severe infection had no significant impact on disease progression. Other than reported for the ip, in this host PA28α/β is dispensable to meet the demand of increased peptide hydrolysis capacity by the proteasome during viral myocarditis.</description><subject>Animals</subject><subject>Antigen Presentation</subject><subject>Antigen processing</subject><subject>Antigens</subject><subject>Autoantigens - immunology</subject><subject>Biology and Life Sciences</subject><subject>Cardiomyocytes</subject><subject>Coxsackievirus infections</subject><subject>Coxsackievirus Infections - immunology</subject><subject>Coxsackievirus Infections - metabolism</subject><subject>Coxsackievirus Infections - virology</subject><subject>Coxsackieviruses</subject><subject>Cytokines</subject><subject>Enterovirus</subject><subject>Enterovirus B, Human - immunology</subject><subject>Epitopes</subject><subject>Female</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Heart</subject><subject>Heart diseases</subject><subject>Homeostasis</subject><subject>Infections</subject><subject>Interferon</subject><subject>Laboratory animals</subject><subject>Major histocompatibility complex</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Myocarditis</subject><subject>Myocarditis - 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During coxsackievirus B3 (CVB3) myocarditis, IFN-induced formation of immunoproteasomes (ip) is known to be critical for regulating immune modulating molecules. The function of the IFN-γ-inducible proteasome regulator subunits PA28 α and β, however, in this context was unknown. During viral myocarditis, we found an increased abundance of PA28β subunits in heart tissue. PA28α/β exists in PA28-20S-PA28 and PA700-20S-PA28 hybrid proteasome complexes in cells both with either predominant ip and standard proteasome (sp) expression. Being in line with reduced proteasome activity in PA28α/β-deficient cells, we observed increased levels of oxidized and poly-ubiquitinated proteins upon TLR3-activation in these cells. Moreover, PA28α/β is capable to interfere directly with viral replication of CVB3 and facilitates the generation of CVB3-derived MHC class I epitopes by the proteasome. In contrast to a distinct function of PA28α/β in vitro, gene ablation of PA28α/β in mice being on a genetic background with resistance towards the development of severe infection had no significant impact on disease progression. Other than reported for the ip, in this host PA28α/β is dispensable to meet the demand of increased peptide hydrolysis capacity by the proteasome during viral myocarditis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28278207</pmid><doi>10.1371/journal.pone.0173259</doi><tpages>e0173259</tpages><orcidid>https://orcid.org/0000-0002-1826-5248</orcidid><oa>free_for_read</oa></addata></record> |
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| issn | 1932-6203 1932-6203 |
| language | eng |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Animals Antigen Presentation Antigen processing Antigens Autoantigens - immunology Biology and Life Sciences Cardiomyocytes Coxsackievirus infections Coxsackievirus Infections - immunology Coxsackievirus Infections - metabolism Coxsackievirus Infections - virology Coxsackieviruses Cytokines Enterovirus Enterovirus B, Human - immunology Epitopes Female Genetic aspects Health aspects Heart Heart diseases Homeostasis Infections Interferon Laboratory animals Major histocompatibility complex Medicine and Health Sciences Mice Mice, Inbred C57BL Mice, Knockout Myocarditis Myocarditis - immunology Myocarditis - metabolism Myocarditis - virology Oxidative stress Peptides Physiology Picornaviridae Proteasome Endopeptidase Complex - immunology Proteasome Endopeptidase Complex - metabolism Proteasome Endopeptidase Complex - physiology Proteasomes Proteins Replication Research and analysis methods Stem cells Studies TLR3 protein Toll-like receptors Ubiquitin-proteasome system Virus Replication γ-Interferon |
| title | PA28 modulates antigen processing and viral replication during coxsackievirus B3 infection |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T07%3A23%3A49IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=PA28%20modulates%20antigen%20processing%20and%20viral%20replication%20during%20coxsackievirus%20B3%20infection&rft.jtitle=PloS%20one&rft.au=Respondek,%20Dorota&rft.date=2017-03-09&rft.volume=12&rft.issue=3&rft.spage=e0173259&rft.epage=e0173259&rft.pages=e0173259-e0173259&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0173259&rft_dat=%3Cgale_plos_%3EA484740208%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1875841164&rft_id=info:pmid/28278207&rft_galeid=A484740208&rft_doaj_id=oai_doaj_org_article_dd4b5fceddb149f682bb04c1cccb1de0&rfr_iscdi=true |