title: Immunoproteasomes largely replace constitutive proteasomes during an antiviral and antibacterial immune response in the liver.
abstract: The proteasome is critically involved in the production of MHC class I-restricted T cell epitopes. Proteasome activity and epitope production are altered by IFN-gamma treatment, which leads to a gradual replacement of constitutive proteasomes by immunoproteasomes in vitro. However, a quantitative analysis of changes in the steady state subunit composition of proteasomes during an immune response against viruses or bacteria in vivo has not been reported. Here we show that the infection of mice with lymphocytic choriomeningitis virus or Listeria monocytogenes leads to an almost complete replacement of constitutive proteasomes by immunoproteasomes in the liver within 7 days. Proteasome replacements were markedly reduced in IFN-gamma(-/-) mice, but were only slightly affected in IFN-alphaR(-/-) and perforin(-/-) mice. The proteasome regulator PA28alpha/beta was up-regulated, whereas PA28gamma was reduced in the liver of lymphocytic choriomeningitis virus-infected mice. Proteasome replacements in the liver strongly altered proteasome activity and were unexpected to this extent, since an in vivo half-life of 12 days had been previously assigned to constitutive proteasomes in the liver. Our results suggest that during the peak phase of viral and bacterial elimination the antiviral cytotoxic T lymphocyte response is directed mainly to immunoproteasome-dependent T cell epitopes, which would be a novel parameter for the design of vaccines.
authors.affiliation: Research Department and Institute for Pathology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Khan
authors.forename: M
authors.initials: M
authors.lastname: van den Broek
authors.forename: K
authors.initials: K
authors.lastname: Schwarz
authors.forename: R
authors.initials: R
authors.lastname: de Giuli
authors.forename: P A
authors.initials: PA
authors.lastname: Diener
authors.forename: M
authors.initials: M
authors.lastname: Groettrup
mesh_terms: D000818:Animals; D001117:Arenaviridae Infections / Q000201:enzymology / Q000276:immunology*; D001324:Autoantigens; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D016898:Interferon-alpha / Q000502:physiology; D007371:Interferon-gamma / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D008088:Listeriosis / Q000201:enzymology / Q000276:immunology*; D008107:Liver Diseases / Q000201:enzymology / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D009687:Nuclear Proteins / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D046988:Proteasome Endopeptidase Complex; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000235:genetics
chemical_list: D001324:Autoantigens; D016898:Interferon-alpha; C099558:Ki antigen; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D052899:Pore Forming Cytotoxic Proteins; D011506:Proteins; D012333:RNA, Messenger; D017471:Receptors, Interferon; D054353:Perforin; C071313:LMP-2 protein; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex