Human Cytomegalovirus Disrupts the Major Histocompatibility Complex Class I Peptide-Loading Complex and Inhibits Tapasin Gene Transcription
- 1 April 2011
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 85 (7), 3473-3485
- https://doi.org/10.1128/jvi.01923-10
Abstract
Major histocompatibility complex class I (MHC I) molecules present antigenic peptides for CD8(+) T-cell recognition. Prior to cell surface expression, proper MHC I loading is conducted by the peptide-loading complex (PLC), composed of the MHC I heavy chain (HC) and β(2)-microglobulin (β(2)m), the peptide transporter TAP, and several chaperones, including tapasin. Tapasin connects peptide-receptive MHC I molecules to the PLC, thereby facilitating loading of high-affinity peptides onto MHC I. To cope with CD8(+) T-cell responses, human cytomegalovirus (HCMV) encodes several posttranslational strategies inhibiting peptide transport and MHC I biogenesis which have been studied extensively in transfected cells. Here we analyzed assembly of the PLC in naturally HCMV-infected fibroblasts throughout the protracted replication cycle. MHC I incorporation into the PLC was absent early in HCMV infection. Subsequently, tapasin neosynthesis became strongly reduced, while tapasin steady-state levels diminished only slowly in infected cells, revealing a blocked synthesis rather than degradation. Tapasin mRNA levels were continuously downregulated during infection, while tapasin transcripts remained stable and long-lived. Taking advantage of a novel method by which de novo transcribed RNA is selectively labeled and analyzed, an immediate decline of tapasin transcription was seen, followed by downregulation of TAP2 and TAP1 gene expression. However, upon forced expression of tapasin in HCMV-infected cells, repair of MHC I incorporation into the PLC was relatively inefficient, suggesting an additional level of HCMV interference. The data presented here document a two-pronged coordinated attack on tapasin function by HCMV.Keywords
This publication has 71 references indexed in Scilit:
- The HCMV membrane glycoprotein US10 selectively targets HLA-G for degradationThe Journal of Experimental Medicine, 2010
- Calreticulin-dependent recycling in the early secretory pathway mediates optimal peptide loading of MHC class I moleculesThe EMBO Journal, 2009
- The redox activity of ERp57 is not essential for its functions in MHC class I peptide loadingProceedings of the National Academy of Sciences of the United States of America, 2008
- High-resolution gene expression profiling for simultaneous kinetic parameter analysis of RNA synthesis and decayRNA, 2008
- Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblastsBlood, 2006
- TAPASIN, DAXX, RGL2, HKE2 and four new genes (BING 1, 3 to 5) form a dense cluster at the centromeric end of the MHCJournal of Molecular Biology, 1998
- Roles for Calreticulin and a Novel Glycoprotein, Tapasin, in the Interaction of MHC Class I Molecules with TAPImmunity, 1996
- The Human Cytomegalovirus US11 Gene Product Dislocates MHC Class I Heavy Chains from the Endoplasmic Reticulum to the CytosolCell, 1996
- Gene disruption in Escherichia coli: TcR and KmR cassettes with the option of Flp-catalyzed excision of the antibiotic-resistance determinantGene, 1995
- Functional expression and purification of the ABC transporter complex associated with antigen processing (TAP) in insect cellsFEBS Letters, 1994