Human papillomaviruses and the specificity of PDZ domain targeting

Abstract

The human papillomavirus (HPV) E6 oncoprotein is fundamental to the ability of these viruses to induce human malignancy. A defining characteristic of the HPV E6 oncoproteins found in cancer‐causing HPV types is the presence of a PDZ binding motif at their extreme C‐terminus. Through this motif, E6 is able to interact with a large number of cellular proteins that contain PDZ domains. Many of these cellular proteins are involved in regulation of processes associated with the control of cell attachment, cell proliferation, cell polarity and cell signaling. How E6 targets multiple proteins containing the same recognition domain is still an open question. In this review, we highlight aspects of E6 function and biology that help to answer this question, and thereby provide insight into the role of these substrates during development of HPV‐induced malignancy.

Disc large 1 expression is altered by human papillomavirus E6/E7 proteins in organotypic cultures of human keratinocytes

“…S2). In these experimental conditions HPV-18 E6 was shown to promote the degradation of DLG1 in a PDZ-binding motif-dependent manner (Gardiol et al, 1999;Pim et al, 2012). However, it is important to understand the regulation of PDZ proteins in the context of HPV infection, where both oncoproteins are expressed together.…”

“…One of the reported oncogenic activities of E6 from high-risk HPV types is its capacity to interact with a select group of PDZ domain-containing proteins, including DLG1, through the C-terminal class 1 PDZ-binding motif (X-S/ T-X-V/L) (Gardiol et al, 1999;Pim et al, 2012). This interaction results in DLG1 protein degradation and/or alteration of subcellular distribution, depending on the experimental conditions and HPV type.…”

Signalling at tight junctions during epithelial differentiation and microbial pathogenesis

“…Similarly, the E6 oncoprotein of high-risk human papillomavirus has the potential to interact with and disrupt several polarity proteins and junctional adaptors that contain a PDZ domain, thus disrupting tight junction assembly. This is thought to confer the transforming capability of this virus (Facciuto et al, 2014;Gardiol et al, 1999;Glaunsinger et al, 2000;Hernández-Monge et al, 2013;Javier, 2008;Latorre et al, 2005;Lee et al, 2000;Nakagawa and Huibregtse, 2000;Pim et al, 2012;Storrs and Silverstein, 2007;Thomas et al, 2008). Another example is the NS1 protein of the avian influenza A virus, which binds to multiple PDZ proteins, including the tight junction adaptors MAGI1, MAGI2 and MAGI3.…”

Convergent evolution and mimicry of protein linear motifs in host–pathogen interactions

“…The association may be inferred from purely statistical correlation between motif repertoire and phenotypic traits [62 ,67,68,73], such as the correspondence between the motif repertoire in the HIV proteome and response of patients to antiretroviral therapy [73]. The association may be further strengthened by experimental demonstration of biochemical properties modulated by the motif [26,69,71,72]. For example, specific substitutions in E7 proteins of high-risk oncogenic types, compared to low-risk types, lead to 30-fold increases in the thermodynamic and kinetic stability of the complexes formed between E7 and the retinoblastoma cell cycle regulator [26].…”

“…Linear motif repertoire has been linked to changes in viral phenotypic traits such as virulence [65][66][67], persistence [68,69,70 ] tropism [62 ], oncogenicity [26,71,72], and response to therapy [73]. The association may be inferred from purely statistical correlation between motif repertoire and phenotypic traits [62 ,67,68,73], such as the correspondence between the motif repertoire in the HIV proteome and response of patients to antiretroviral therapy [73].…”