E3/19K from adenovirus 2 is an immunosubversive protein that binds to a structural motif regulating the intracellular transport of major histocompatibility complex class I proteins.
We have previously expressed in transgenic mice a chimeric H-2Kd/Kk protein called C31, which contains the extracellular alpha 1 domain of Kd, whereas the rest of the molecule is of Kk origin. This molecule functions as a restriction element for alloreactive and influenza A-specific cytotoxic T lymphocytes (CTL) but is only weakly expressed at the cell surface of splenocytes. Here, we show that the low cell surface expression is the result of slow intracellular transport and processing of the C31 protein. A set of hybrid molecules between Kd and Kk were used to localize the regions in major histocompatibility complex (MHC) molecules that are important for their intracellular transport and to further localize the structures responsible for binding to the adenovirus 2 E3/19K protein. This protein appears to be an important mediator of adenovirus persistence. It acts by binding to the immaturely glycosylated forms of MHC class I proteins in the endoplasmic reticulum (ER), preventing their passage to the cell surface and thereby reducing the recognition of infected cells by virus-specific T cells. We find the surprising result that intracellular transport and E3/19K binding are controlled primarily by the first half of the second domain of Kd, thus localizing these phenomena to the five polymorphic residues in this region of the Kd protein. This result implies that the E3/19K protein may act by inhibiting peptide binding or by disrupting the oligomerization of MHC class I molecules required for transport out of the ER. Alternatively, the E3/19K protein may inhibit the function of a positively acting transport molecule necessary for cell surface expression of MHC class I molecules.
Jefferies
W A
WA
Department of Microbiology, University of British Columbia, Vancouver, Canada.
Burgert
H G
HG
D017503:Adenovirus E3 Proteins; D000260:Adenoviruses, Human / Q000276:immunology*; D000818:Animals; D000906:Antibodies; D002460:Cell Line; D005434:Flow Cytometry; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D007700:Kinetics; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D013154:Spleen / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology*
D017503:Adenovirus E3 Proteins; D000906:Antibodies; C066649:C31 protein, mouse; D006183:H-2 Antigens; D015395:Histocompatibility Antigens Class I; D014764:Viral Proteins