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Journal of Virology, February 2004, p. 1831-1842, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.1831-1842.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

A Cytomegalovirus Inhibitor of Gamma Interferon Signaling Controls Immunoproteasome Induction

Selina Khan,^1, Albert Zimmermann,² Michael Basler,³ Marcus Groettrup,^1,3* and Hartmut Hengel^2*

Research Department, Cantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland,¹ Division of Viral Infections, Robert Koch-Institut, Nordufer 20, D-13353 Berlin,² Division of Immunology, Department of Biology, University of Constance, D-78457 Konstanz, Germany³

Received 8 July 2003/ Accepted 24 October 2003

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-)-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--inducible proteasome regulator PA28ß 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- 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.

Present address: Department of Immunohematology and Blood Bank, University Hospital, 2300 RC Leiden, The Netherlands.

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