Down-regulation of MHC class I by bovine papillomavirus E5 oncoproteins

Abstract

The papillomavirus E5 protein is localized in the endoplasmic reticulum (ER) and Golgi apparatus (GA) of the host cell. Transformed bovine ®broblasts expressing bovine papillomavirus (BPV) E5 are highly vacuolated and have a much enlarged, distorted and fragmented GA. Major histocompatibility complex class I (MHC I) is processed and transported to the cell surface through the GA. Given the cellular localization of E5 in the GA and the morphologically abnormal GA, we investigated the expression of MHC I in cells transformed by E5 from BPV-1 and BPV-4. Two cell lines were used: bovine cells that also express E6, E7 and activated ras, and NIH3T3 cells that express only E5. In addition, PalF cells acutely infected with a recombinant retrovirus expressing E5 were also examined. In contrast to non-transformed normal cells, or transformed cells expressing other papillomavirus proteins, cells expressing E5 do not express MHC I on their surface, but retain it intracellularly, independently of the presence of other viral or cellular oncogenes, or of whether the cells are long-term transformants or acutely infected. We conclude that expression of E5 prevents expression of MHC I to the cell surface and causes its retention within the cell. In addition, lower amounts of total MHC I heavy chain and of heavy chain RNA are detected in E5-transformed cells than in control cells. As surface expression of another glycosylated membrane protein, the transferrin receptor, is not aected, it appears that E5 targets MHC I with at least a degree of speci®city. In papillomavirus lesions this eect would have important implications for antigen presentation by, and immunosurveillance of, virally infected cells.

Bovine papillomaviruses, papillomas and cancer in cattle

“…Thus, the ability of E5 to perturb the pH of intracellular organelles may influence the activity of many proteins and contribute to cell transformation. An important consequence of E5 mediated impaired acidification is the down-regulation (both in vivo and in vitro) of Major Histocompatibility Complex class I (MHC-I) expression, representing one of the mechanisms by which BPV evades the host's immunoresponse [9]. Down-regulation of MHC-I takes place at multiple levels: the transcription of the gene is reduced, the MHC-I heavy chain peptide is degraded [9] and the MHC-I complex is sequestered in the GA cisternae and prevented from reaching the cell surface [81].…”

“…An important consequence of E5 mediated impaired acidification is the down-regulation (both in vivo and in vitro) of Major Histocompatibility Complex class I (MHC-I) expression, representing one of the mechanisms by which BPV evades the host's immunoresponse [9]. Down-regulation of MHC-I takes place at multiple levels: the transcription of the gene is reduced, the MHC-I heavy chain peptide is degraded [9] and the MHC-I complex is sequestered in the GA cisternae and prevented from reaching the cell surface [81]. The molecular mechanism by which BPV-1 E5 induces cell transformation lies in its binding to, and activation of, the cellular receptor for the platelet-derived growth factor (PDGF ) [48].…”

E5 protein of human papillomavirus type 16 selectively downregulates surface HLA class I

“…10,11 We have shown that one of the outcomes of BPV E5 expression in primary cells is the retention of major histocompatibility (MHC) class I complexes in the GA and the inhibition of their transport to the cell surface. 12,13 Furthermore, BPV E5 inhibits both transcription of the MHC class I heavy chain gene and affects the stability of the heavy chain protein. 12 In this study, we show that HPV-16 E5 also prevents the transport of MHC (HLA) class I complexes to the cell surface due to retention in the GA.…”

Presence of bovine papillomavirus type 2 DNA and expression of the viral oncoprotein E5 in naturally occurring urinary bladder tumours in cows

“…E5 is a small hydrophobic protein (44 aa) that is capable of inducing in vitro cell transformation through the activation of several kinases, from growth factor receptors to cdk cyclins (Venuti & Campo, 2002). E5 interacts physically with the cellular protein 16k ductin/ subunit c, a component of the gap junction and of the V0 sector of vacuolar H + -ATPase (Conrad et al, 1993;Faccini et al, 1996;Finbow et al, 1991;Goldstein et al, 1991), causing the downregulation of gap junction communication (Ashrafi et al, 2002;Faccini et al, 1996;Oelze et al, 1995) and the lack of acidification of endosomes and Golgi apparatus (GA) (Schapiro et al, 2000;Straight et al, 1995). However, its function in vivo is still unknown.…”

“…It has been suggested that cancer cells may escape host immune control by E5-mediated downregulation of MHC class I molecules. This downregulation seems to be related to the interaction of E5 with 16k ductin/subunit c, which may lead to improper glycosylation and processing of MHC class I molecules (Marchetti et al, 2002). Since the cows from which we collected the samples had been grazing on bracken fern-infested pasture, the immunosuppression caused by the plant could enhance the escape of the E5-expressing tumour cells from the immune system.…”