Abstract
Cytomegaloviruses (CMVs) are ubiquitous pathogens known to employ numerous immunoevasive strategies that significantly impair the ability of the immune system to eliminate the infected cells. Here, we report that the single mouse CMV (MCMV) protein, m154, downregulates multiple surface molecules involved in the activation and costimulation of the immune cells. We demonstrate that m154 uses its cytoplasmic tail motif, DD, to interfere with the adaptor protein-1 (AP-1) complex, implicated in intracellular protein sorting and packaging. As a consequence of the perturbed AP-1 sorting, m154 promotes lysosomal degradation of several proteins involved in T cell costimulation, thus impairing virus-specific CD8+ T cell response and virus control in vivo. Additionally, we show that HCMV infection similarly interferes with the AP-1 complex. Altogether, we identify the robust mechanism employed by single viral immunomodulatory protein targeting a broad spectrum of cell surface molecules involved in the antiviral immune response.
| Original language | American English |
|---|---|
| Article number | e50803 |
| Journal | eLife |
| Volume | 9 |
| DOIs | |
| State | Published - Jan 2020 |
Bibliographical note
Funding Information:We thank Suzana Malic, Karmela Miklic, Edvard Razic, and Dijana Rumora for excellent technical assistance in biochemical methods, monoclonal antibody production and virus production. We also thank Miro Samsa, Edvard Marinovic, Ante Mise and Maja Cokaric Brdovcak for assistance in breeding and handling animals. We thank Annette Oxenius (Institute of Microbiology, ETH Zürich, Zürich, Switzerland) for providing the Maxi mice. The following reagents were obtained through the National Institutes of Health (NIH) Tetramer Core Facility: MCMV-specific tetramer pp89-PE, MCMV pp89-derived peptide. Guillem Angulo was supported by a fellowship ‘Formación de Personal Inves-tigador’ from the Ministerio de Economía y Competitividad (MINECO, Spain). Funding Acquisition, AA (Ministerio de Economía y Competitividad (MINECO, Spain) grant no. SAF2017-87688), TLR (Croatian Science Foundation grant no. UIP-11-2013-1533; University of Rijeka grant no. uniri- biomed-18–23), SJ (“Strengthening the capacity of CerVirVac for research in virus immunology and vaccinology“, grant no. KK.01.1.1.01.0006, awarded to the Scientific Centre of Excellence for Virus Immunology and Vaccines and co-financed by the European Regional Development Fund). The funding sources were not involved in study design, data collection and interpretation, or the decision to submit the work for publication
Funding Information:
We thank Suzana Malic, Karmela Miklic, Edvard Razic, and Dijana Rumora for excellent technical assistance in biochemical methods, monoclonal antibody production and virus production. We also thank Miro Samsa, Edvard Marinovic, Ante Mise and Maja Cokaric Brdovcak for assistance in breeding and handling animals. We thank Annette Oxenius (Institute of Microbiology, ETH Z?rich, Z?rich, Switzerland) for providing the Maxi mice. The following reagents were obtained through the National Institutes of Health (NIH) Tetramer Core Facility: MCMV-specific tetramer pp89-PE, MCMV pp89-derived peptide. Guillem Angulo was supported by a fellowship ?Formaci?n de Personal Inves-tigador? from the Ministerio de Econom?a y Competitividad (MINECO, Spain). Funding Acquisition, AA (Ministerio de Econom?a y Competitividad (MINECO, Spain) grant no. SAF2017-87688), TLR (Croatian Science Foundation grant no. UIP-11-2013-1533; University of Rijeka grant no. uniri-. Ministerio de Econom?a y Competitividad. SAF2017-87688. Ana Angulo. Hrvatska Zaklada za Znanost. UIP-11-2013-1533. Tihana Lenac Rovis. European Regional Development Fund. KK.01.1.1.01.0006. Stipan Jonjic biomed-18?23), SJ (?Strengthening the capacity of CerVirVac for research in virus immunology and vaccinology?, grant no. KK.01.1.1.01.0006, awarded to the Scientific Centre of Excellence for Virus Immunology and Vaccines and co-financed by the European Regional Development Fund). The funding sources were not involved in study design, data collection and interpretation, or the decision to submit the work for publication.
Publisher Copyright:
© Strazic Geljic et al.