A cytomegalovirus inhibitor of gamma interferon signaling controls immunoproteasome induction.
Both human and mouse cytomegaloviruses (HCMV and MCMV) avoid peptide presentation through the major histocompatibility complex (MHC) class I pathway to CD8(+) T cells. Within the MHC class I pathway, the vast majority of antigenic peptides are generated by the proteasome system, a multicatalytic protease complex consisting of constitutive subunits, three of which can be replaced by enzymatically active gamma interferon (IFN-gamma)-inducible subunits, i.e., LMP2, LMP7, and MECL1, to form the so-called immunoproteasomes. Here, we show that steady-state levels of immunoproteasomes are readily formed in response to MCMV infection in the liver. In contrast, the incorporation of immunoproteasome subunits was prevented in MCMV-infected, as well as HCMV-infected, fibroblasts in vitro. Likewise, the expression of the IFN-gamma-inducible proteasome regulator PA28 alpha beta was also impaired in MCMV-infected cells. Both MCMV and HCMV did not alter the constitutive-subunit composition of proteasomes in infected cells. Quantitative assessment of LMP2, MECL1, and LMP7 transcripts revealed that the inhibition of immunoproteasome formation occurred at a pretranscriptional level. Remarkably, a targeted deletion of the MCMV gene M27, encoding an inhibitor of STAT2 that disrupts IFN-gamma receptor signaling, largely restored transcription and protein expression of immunoproteasome subunits in infected cells. While CMV block peptide transport and MHC class I assembly by posttranslational strategies, immunoproteasome assembly, and thus the repertoire of proteasomal peptides, is controlled by pretranscriptional mechanisms. We hypothesize that the blockade of immunoproteasome formation has considerable consequences for shaping the CD8(+)-T-cell repertoire during the effector phase of the immune response.
Khan
Selina
S
Research Department, Cantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland.
Zimmermann
Albert
A
Basler
Michael
M
Groettrup
Marcus
M
Hengel
Hartmut
H
D000818:Animals; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000096:biosynthesis* / Q000276:immunology; D003587:Cytomegalovirus / Q000378:metabolism / Q000472:pathogenicity*; D003586:Cytomegalovirus Infections / Q000276:immunology; D004790:Enzyme Induction; D005260:Female; D005347:Fibroblasts; D005786:Gene Expression Regulation; D006566:Herpesviridae Infections / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000378:metabolism / Q000472:pathogenicity*; D015398:Signal Transduction / Q000187:drug effects; D014764:Viral Proteins / Q000378:metabolism* / Q000494:pharmacology
D014764:Viral Proteins; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases