From: hrHPV E5 oncoprotein: immune evasion and related immunotherapies
E5 activity | Mechanism |
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Disruption of the transport of MHC I to the surface, reduction of antigen presentation to CTL cells and NK-mediated response. | E5 prevents the transport of MHC I (HLA-A and –B) to the surface membrane in three significant ways: i) it impairs Golgi Apparatus acidification which causes the accumulation of MHC I in this organelle [5]; ii) it binds to Bap31 (B-cell-associated protein 31), by displacing this protein from MHC I and causing the retention of this molecule in ER/GA [136]; iii) and it interacts with the MHC I heavy chain, via leucine pairs [5]. |
MHC I and MHC II downregulation. | By impairing MHC I [36] and II [44] gene expression, E5 supports HPV immune evasion. |
Inhibition of CD1d-mediated activities. | E5 binds to calnexin and thus traps the CD1d molecule into the endoplasmic reticulum, reducing CD1d levels at the membrane surface [42, 137]. |
Increase of EGF-R availability causing an upregulation of COX2, VEGF and inducing cell proliferation. | E5 binds and inhibits the activity of V-ATPase, impairs endosomal acidification and causes the degradation of EGF-R. It also enhances EGF-R recycling at the plasma membrane [138, 139]; it also delays EGF-R degradation owing to interference with membrane trafficking [3] and interaction with c-Cbl, provoking decrease of c-Cbl-mediated degradation of EGF-R [140]. These activities cause upregulation of COX2 [49], which is an essential enzyme for inflammatory response, and VEGF, an angiogenic factor [141]. |
EGF-R-dependent or -independent activation of signaling pathways. | E5 activates MAPK, p38 and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) independently of EGF-R activation, which increases the expression of c-fos and c-jun (types of AP-1) and stimulates the transcription of E6 and E7 oncogenes [6, 23, 142]. Besides, it impedes several host immune protective activities. E5 can also bind directly to EGF-R and other growth factor receptors by hydrophobic interactions and induce the ligand-dependent signaling of these receptors [143]. |
Activation of gene expression of caveolin-1 and ganglioside-1. | Caveolin-1 and GM-1 are upregulated in the plasma membrane, and support viral immune evasion [47]. |
Upregulation of IFN-β. | IFN-β gene expression is induced by E5 by inducing the increase of IFN regulatory factor-1 (IRF-1) levels in infected cells [90]. |
Down-regulation of TGF-β-RII gene expression and TGF-β\SMAD signaling. | E5 attenuates TGF-β/SMAD-signalling by preventing TGF-β-RII gene expression. It also reduces SMAD phosphorylation and nuclear translocation [68]. |