title: PA28 modulates antigen processing and viral replication during coxsackievirus B3 infection.
abstract: 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.
authors.affiliation: Institut für Biochemie, Charité Universitätsmedizin Berlin, Berlin, Germany.|DZHK (German Centre for Cardiovascular Research), partner side Berlin, Berlin, Germany.
authors.forename: Dorota
authors.initials: D
authors.lastname: Respondek
authors.affiliation: Institut für Biochemie, Charité Universitätsmedizin Berlin, Berlin, Germany.|DZHK (German Centre for Cardiovascular Research), partner side Berlin, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Voss
authors.affiliation: Institut für Biochemie, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Kühlewindt
authors.affiliation: Institut für Molekulare Pathologie, Universitätsklinikum Tübingen, Tübingen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Klingel
authors.affiliation: Institut für Biochemie, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Krüger
authors.affiliation: Institut für Biochemie, Charité Universitätsmedizin Berlin, Berlin, Germany.|DZHK (German Centre for Cardiovascular Research), partner side Berlin, Berlin, Germany.
authors.forename: Antje
authors.identifier: http://orcid.org/0000-0002-1826-5248
authors.initials: A
authors.lastname: Beling
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D001324:Autoantigens / Q000276:immunology; D003384:Coxsackievirus Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D029822:Enterovirus B, Human / Q000276:immunology*; D000939:Epitopes; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D046988:Proteasome Endopeptidase Complex / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D014779:Virus Replication
chemical_list: D001324:Autoantigens; D000939:Epitopes; C085834:PA700 proteasome activator; C486207:PSME2 protein, human; D046988:Proteasome Endopeptidase Complex; C486213:Psme1 protein, mouse