Emerging Theme: Cellular PDZ Proteins as Common Targets of Pathogenic Viruses

Abstract

More than a decade ago, three viral oncoproteins, adenovirus type 9 E4-ORF1, human T-lymphotropic virus type 1 Tax, and high-risk human papillomavirus E6, were found to encode a related carboxyl-terminal PDZ domain-binding motif (PBM) that mediates interactions with a select group of cellular PDZ proteins. Recent studies have shown that many other viruses also encode PBM-containing proteins that bind to cellular PDZ proteins. Interestingly, these recently recognized viruses include not only some with oncogenic potential (hepatitis B virus, rhesus papillomavirus, cottontail rabbit papillomavirus) but also many without this potential (influenza virus, Dengue virus, tick-borne encephalitis virus, rabies virus, severe acute respiratory syndrome coronavirus, human immunodeficiency virus). Examination of the cellular PDZ proteins that are targets of viral PBMs reveals that the viral proteins often interact with the same or similar types of PDZ proteins, most notably Dlg1 and other members of the membrane-associated guanylate kinase protein family, as well as Scribble. In addition, cellular PDZ protein targets of viral PBMs commonly control tight junction formation, cell polarity establishment, and apoptosis. These findings reveal a new theme in virology wherein many different virus families encode proteins that bind and perturb the function of cellular PDZ proteins. The inhibition or perturbation of the function of cellular PDZ proteins appears to be a widely used strategy for viruses to enhance their replication, disseminate in the host, and transmit to new hosts.The PDZ domain is a protein-protein interaction module that is widespread throughout evolution, being found in bacteria, fungi, and metazoans (76). PDZ domains generally consist of approximately 90 amino acid residues that adopt a structure composed of six ␤-strands and two ␣-helices (reviewed in reference 57). The term PDZ is an abbreviation for the first three proteins found to share this structural domain: PSD-95, Dlg, and ZO-1. PDZ domains are typically found in cytoplasmic and membrane adapter proteins that are involved in a variety of cellular processes of significance to viral infection: maintenance of cell-cell junctions, cellular polarity, and signal transduction pathways. In metazoans, PDZ proteins often contain multiple PDZ domains and additional proteinprotein interaction elements, such as SH3, L27, or leucine-rich repeat (LRR) domains. In the mouse genome, over 700 individual PDZ domains are found in over 300 proteins, while in the human genome, over 900 PDZ domains are found in over

Comprehensive Analysis of Host Cellular Interactions with Human Papillomavirus E6 Proteins Identifies New E6 Binding Partners and Reflects Viral Diversity

“…Both the function and the nature of interactions between beta E6s and PDZ domain proteins have yet to be determined. It should be noted that interactions with proteins containing PDZ domains are not restricted to oncogenic viruses, that these interactions may contribute important functions to the replication of viruses even in the absence of a tumorigenic function (29), and also that HPV8 E6 was recently shown to inhibit expression of the PDZ protein Syntenin 2 at the level of transcription (36).…”

Biology of Human Papillomavirus Infections in Head and Neck Carcinogenesis

“…5). The HPV E7 protein can induce cellular proliferation through several pathways by disrupting the activity of cyclin-dependent kinase (CDK) inhibitors p21 and p27, activation of CDKs and destabilization of the Rb tumor suppressor protein [for review see [20][21][22][23][24]. Rb family members (pRb, p107, p130) are instrumental in the control of cell cycle progression largely through regulation of the E2F family of transcription factors [23,25].…”

“…The tight control of viral gene expression and function during infection is critical both for completion of the viral life cycle and for preventing malignant transformation. The activity of E7 can be controlled through a direct interaction with E2, resulting in an inhibition of transforming activity of E7 [20][21][22][23][24][25].…”

“…The HPV E7 gene can immortalize human keratinocytes alone when expressed at high levels [for review see 24,34,35]. E7 protein of the low-risk HPV types also binds to pRb, although with lower affinity, but thus indicating its significance in transformation.…”

Scribble regulates an EMT–polarity pathway through modulation of MAPK-ERK signaling to mediate junction formation

“…HPV is frequently associated with cervical carcinomas, which often show decreased Scribble expression (Nakagawa et al, 2004). Other oncogenic viruses such as human T-cell leukemia virus type 1 (HTLV-1) Tax, a causative agent for adult T-cell leukemia, are known to target Scribble (Elsum et al, 2012;Javier and Rice, 2011;Okajima et al, 2008). Additionally, mislocalization or deregulated Scribble expression has been reported in a variety of epithelial cancers (Gardiol et al, 2006;Kamei et al, 2007;Navarro et al, 2005;Ouyang et al, 2010;Pearson et al, 2011;Vaira et al, 2011;Zhan et al, 2008).…”