title: A short isoform of human cytomegalovirus US3 functions as a dominant negative inhibitor of the full-length form.
abstract: 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 the US3 gene 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 the US3 locus 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.
authors.affiliation: Department of Biological Sciences, Seoul National University, San 56-1, Sillim-dong, Gwanak-Gu, Seoul 151-747, Korea.
authors.forename: Jinwook
authors.initials: J
authors.lastname: Shin
authors.forename: Boyoun
authors.initials: B
authors.lastname: Park
authors.forename: Sungwook
authors.initials: S
authors.lastname: Lee
authors.forename: Youngkyun
authors.initials: Y
authors.lastname: Kim
authors.forename: Bonita J
authors.initials: BJ
authors.lastname: Biegalke
authors.forename: Seongman
authors.initials: S
authors.lastname: Kang
authors.forename: Kwangseog
authors.initials: K
authors.lastname: Ahn
mesh_terms: D003587:Cytomegalovirus / Q000276:immunology / Q000502:physiology*; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D006023:Glycoproteins; D015395:Histocompatibility Antigens Class I; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; C095111:US3 protein, cytomegalovirus