Abstract
The human papillomavirus type 16 E5 protein (HPV16 E5) down-regulates surface expression of HLA-I molecules. The molecular mechanisms underlying this effect are so far unknown. Here we show that HPV16 E5 down-regulates HLA-I surface expression in calnexin-containing but not in calnexin-deficient cells. Immunoprecipitation experiments reveal that calnexin and HPV16E5 can be co-precipitated and that this association depends on the presence of a wild-type first hydrophobic region of E5. When an E5 mutant (M1) in which the first putative transmembrane helix had been disrupted was used for the transfections calnexin-E5 co-precipitation was strongly impaired. In addition, we show that the M1 mutant is only able to marginally down-regulate HLA-I surface expression compared to the wild-type protein. Besides, we demonstrate that E5 forms a ternary complex with calnexin and the heavy chain of HLA-I, which is mediated by the first hydrophobic region of the E5 protein. On the basis of our results we conclude that formation of this complex is responsible for retention of HLA-I molecules in the ER of the cells.
Highlights
Epidemiological analyses have demonstrated a close association between infection of certain human papillomavirus (HPV) species within the Alphapapillomavirus genus and malignant growth of the human cervix epithelium [13], as HPV sequences have been found in virtually all cervical cancers [4]
HPV16 E5 decreases surface expression of HLA-I molecules Experimental results have shown that BPV E5 as well as HPV16 E5 and HPV2 E5 proteins down-regulate surface expression of HLA-I molecules [22,24,41,42]
These results demonstrate that HPV16 E5 can down-regulate cell surface expression under our experimental conditions
Summary
Epidemiological analyses have demonstrated a close association between infection of certain human papillomavirus (HPV) species within the Alphapapillomavirus genus and malignant growth of the human cervix epithelium [13], as HPV sequences have been found in virtually all cervical cancers [4]. High-risk HPV infection of the stratified epithelium occurs first in the basal cell layer, where transcription of the early genes E5, E6 and E7 takes place [7,8]. Using cellular systems it has been shown that HPV16 E5 expression results in down-regulation of cell surface expression of HLA-I and HLA-II molecules [19,20,21,22]. This down-regulation might result in diminished antigen-presentation and decreased adaptive immunoresponse of the host. The intimate mechanisms responsible for the reduced amount of HLA-I molecules at the cell surface remain still elusive
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