A Short Isoform of Human Cytomegalovirus US3 Functions as a Dominant Negative Inhibitor of the Full-Length Form
| Autor: | Jinwook Shin, Sung-Wook Lee, Seongman Kang, Kwangseog Ahn, Boyoun Park, Young-Kyun Kim, Bonita J. Biegalke |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Gene isoform
biology viruses Histocompatibility Antigens Class I Immunology Alternative splicing Cellular Response to Infection Cytomegalovirus Membrane Proteins Transporter associated with antigen processing Major histocompatibility complex Microbiology Virology Immediate early protein Immediate-Early Proteins Cell biology Tapasin Insect Science MHC class I biology.protein Humans Cytotoxic T cell Glycoproteins HeLa Cells |
| Zdroj: | Journal of Virology. 80:5397-5404 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.02397-05 |
| Popis: | Human cytomegalovirus encodes four unique short (US) region proteins, each of which is independently sufficient for causing the down-regulation of major histocompatibility complex (MHC) class I molecules on the cell surface. This down-regulation enables infected cells to evade recognition by cytotoxic T lymphocytes (CTLs) but makes them vulnerable to lysis by natural killer (NK) cells, which lyse those cells that lack MHC class I molecules. The 22-kDa US3 glycoprotein is able to down-regulate the surface expression of MHC class I molecules by dual mechanisms: direct endoplasmic reticulum retention by physical association and/or tapasin inhibition. The alternative splicing of theUS3gene generates two additional products, including 17-kDa and 3.5-kDa truncated isoforms; however, the functional significance of these isoforms during viral infection is unknown. Here, we describe a novel mode of self-regulation of US3 function that uses the endogenously produced truncated isoform. The truncated isoform itself neither binds to MHC class I molecules nor prevents the full-length US3 from interacting with MHC class I molecules. Instead, the truncated isoform associates with tapasin and competes with full-length US3 for binding to tapasin; thus, it suppresses the action of US3 that causes the disruption of the function of tapasin. Our results indicate that the truncated isoform of theUS3locus acts as a dominant negative regulator of full-length US3 activity. These data reflect the manner in which the virus has developed temporal survival strategies during viral infection against immune surveillance involving both CTLs and NK cells. |
| Databáze: | OpenAIRE |
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