scholarly journals Acquisition of a phospho-acceptor site enhances HPV E6 PDZ-binding motif functional promiscuity

2020 ◽  
Vol 101 (9) ◽  
pp. 954-962 ◽  
Author(s):  
Vanessa Sarabia-Vega ◽  
Lawrence Banks
Keyword(s):  
Protein Recognition ◽  
Binding Motif ◽  
Acceptor Site ◽  
Oncogenic Potential ◽  
Pdz Proteins ◽  
Hpv E6 ◽  
Hpv Types ◽  
Pdz Protein ◽  
Minor Sequence ◽  
Hpv 18

All cancer-causing human papillomavirus (HPV) E6 oncoproteins have a C-terminal PDZ-binding motif (PBM), which correlates with oncogenic potential. Nonetheless, several HPVs with little or no oncogenic potential also have an E6 PBM, with minor sequence differences affecting PDZ protein selectivity. Furthermore, certain HPV types have a phospho-acceptor site embedded within the PBM. We therefore compared HPV-18, HPV-66 and HPV-40 E6 proteins to examine the possible link between the ability to target multiple PDZ proteins and the acquisition of a phospho-acceptor site. The mutation of essential residues in HPV-18E6 reduces its phosphorylation, and fewer PDZ substrates are bound. In contrast, the generation of consensus phospho-acceptor sites in HPV-66 and HPV-40 E6 PBMs increases the PDZ proteins recognized. Thus, although phosphorylation of the E6 PBM and PDZ protein recognition are mutually exclusive, they are closely linked, with the acquisition of a phospho-acceptor site also contributing to an expansion in the number of PDZ proteins bound.

scholarly journals High-Risk Human Papillomavirus E6 Oncoproteins Interact with 14-3-3ζ in a PDZ Binding Motif-Dependent Manner

2012 ◽  
Vol 87 (3) ◽  
pp. 1586-1595 ◽  
Author(s):  
Siaw Shi Boon ◽  
Lawrence Banks
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
High Risk ◽  
Pdz Domain ◽  
Binding Motif ◽  
Dependent Manner ◽  
Hpv E6 ◽  
Hpv Types ◽  
High Risk Hpv ◽  
Hpv 18

ABSTRACTCervical cancer develops through the combined activities of the human papillomavirus (HPV) E6 and E7 oncoproteins. A defining characteristic of E6 oncoproteins derived from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at the extreme carboxy terminus of the protein which is absent from E6 proteins derived from the so-called low-risk HPV types. Within this PBM is also a protein kinase A (PKA) phospho-acceptor site, which is thought to negatively regulate the association of E6 with its PDZ domain-containing substrates. We can now show that phosphorylation of E6 by PKA and/or AKT confers the ability to interact with 14-3-3ζ. The interaction is direct and specific for the high-risk HPV E6 oncoproteins, although there are significant differences in the efficiencies with which HPV-16, HPV-18, and HPV-31 E6 oncoproteins can associate with 14-3-3ζ; this correlates directly with their respective susceptibilities to phosphorylation by PKA and/or AKT. We demonstrate here that the interaction between E6 and 14-3-3ζ also requires integrity of the E6 PBM, and downregulation of 14-3-3ζ results in a marked reduction in the levels of HPV-18 E6 expression in HeLa cells. Using phospho-specific anti-E6 antibodies, we also demonstrate significant levels of E6 phosphorylationin vivo. These studies redefine the potential relevance of the E6 PBM in the development of cervical cancer, suggesting that interaction with 14-3-3ζ, as well as the more well-established interactions with PDZ domain-containing substrates, is likely to be responsible for the biological activities attributed to this region of the high-risk HPV E6 oncoproteins.

scholarly journals PDZRN3/LNX3 Is a Novel Target of Human Papillomavirus Type 16 (HPV-16) and HPV-18 E6

2014 ◽  
Vol 89 (2) ◽  
pp. 1439-1444 ◽  
Author(s):  
Miranda Thomas ◽  
Lawrence Banks
Keyword(s):  
Human Papillomavirus ◽  
Binding Motif ◽  
Dependent Manner ◽  
Hpv 16 ◽  
Cellular Targets ◽  
Ubiquitin Protein Ligase ◽  
Human Papillomavirus Type 16 ◽  
Hpv E6 ◽  
Novel Target ◽  
Hpv 18

High-risk human papillomavirus (HPV) E6 proteins have a C-terminal PDZ binding motif through which they bind, and target for proteasome-mediated degradation, a number of PDZ-containing cellular targets. Recent studies have suggested that the RING-containing ubiquitin-protein ligase PDZRN3 might also be an HPV E6 target. In this analysis, we show that HPV-16 and HPV-18 E6 can target PDZRN3 in a PDZ- and proteasome-dependent manner and provide a connection between the HPV life cycle and differentiation-related STAT signaling.

scholarly journals Cancer-Causing Human Papillomavirus E6 Proteins Display Major Differences in the Phospho-Regulation of Their PDZ Interactions

2014 ◽  
Vol 89 (3) ◽  
pp. 1579-1586 ◽  
Author(s):  
Siaw Shi Boon ◽  
Vjekoslav Tomaić ◽  
Miranda Thomas ◽  
Sally Roberts ◽  
Lawrence Banks
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Signaling Pathways ◽  
Binding Activity ◽  
Binding Potential ◽  
Binding Motif ◽  
Virus Infections ◽  
Hpv E6 ◽  
Hpv Types ◽  
High Risk Hpv

ABSTRACTPrevious studies have shown that the cancer-causing high-risk human papillomavirus (HPV) E6 oncoproteins have PDZ binding potential, an activity which is important for their ability to support the viral life cycle and to cooperate in the induction of malignancy. However, PDZ interactions are not constitutive, and they can be negatively regulated by phosphorylation within the E6 PDZ binding motif (PBM). In this study, we have investigated the differential regulation of the HPV E6 PBMs from diverse high-risk HPV types. We show that, depending on the HPV type, PDZ binding activity can be regulated by phosphorylation with protein kinase A (PKA) or AKT, which, in turn, inhibits PDZ recognition. Such regulation is highly conserved between E6 proteins derived from HPV-16, HPV-18, and HPV-58 while being somewhat weaker or absent from other types such as HPV-31, HPV-33, and HPV-51. In the case of HPV31, PKA phosphorylation occurs within the core of the E6 protein and has no effect on PDZ interactions, and this demonstrates a surprising degree of heterogeneity among the different high-risk HPV E6 oncoproteins in how they are regulated by different cellular signaling pathways.IMPORTANCEThis study demonstrated that the cancer-causing HPV E6 oncoproteins are all subject to posttranslational modification of their extreme C-terminal PDZ binding motifs through phosphorylation. However, the identities of the kinase are not the same for all HPV types. This demonstrates a very important divergence between these HPVs, and it suggests that changes in cell signaling pathways have different consequences for different high-risk virus infections and their associated malignancies.

scholarly journals PDZ Domains and Viral Infection: Versatile Potentials of HPV-PDZ Interactions in relation to Malignancy

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Kazunori Nagasaka ◽  
Kei Kawana ◽  
Yutaka Osuga ◽  
Tomoyuki Fujii
Keyword(s):  
Posttranslational Modifications ◽  
Pdz Domain ◽  
Distribution Patterns ◽  
Spatiotemporal Analysis ◽  
Human Papillomaviruses ◽  
Screening Tools ◽  
Binding Motif ◽  
Normal Epithelium ◽  
Pdz Proteins ◽  
Hpv E6

Cervical cancer is caused by high-risk human papillomaviruses (HPVs), and a unique characteristic of these is a PDZ (P̲SD-95/D̲lg/Z̲O-1-)binding motif in their E6 proteins. Through this motif HPV E6 interacts with a variety of PDZ domain-containing proteins and targets them mainly for degradation. These E6-PDZ interactions exhibit extraordinarily different functions in relation to HPV-induced malignancy, depending upon various cellular contexts; for example, Dlg and Scrib show different distribution patterns from what is seen in normal epithelium, both in localization and in amount, and their loss may be a late-stage marker in malignant progression. Recent studies show that interactions with specific forms of the proteins may have oncogenic potential. In addition, it is interesting that PDZ proteins make a contribution to the stabilization of E6 and viral episomal maintenance during the course of HPV life cycle. Various posttranslational modifications also greatly affect their functions. Phosphorylation of hDlg and hScrib by certain kinases regulates several important signaling cascades, and E6-PDZ interactions themselves are regulated through PKA-dependent phosphorylation. Thus these interactions naturally have great potential for both predictive and therapeutic applications, and, with development of screening tools for identifying novel targets of their interactions, comprehensive spatiotemporal analysis is currently underway.

scholarly journals Prevalence of precancerous cervical lesions and high-risk human papillomavirus types in Yaounde, Cameroon

2021 ◽  
Vol 15 (09) ◽  
pp. 1339-1345
Author(s):  
Richard Tagne Simo ◽  
Arsène G Djoko Nono ◽  
Hervet Paulin Fogang Dongmo ◽  
Paul F Seke Etet ◽  
Bertrand Kiafon Fonyuy ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Precancerous Lesions ◽  
Health Centre ◽  
Oral Contraceptive Pill ◽  
Cervical Lesions ◽  
Hpv 16 ◽  
Hpv Types ◽  
Cytologic Abnormalities ◽  
Hpv 18

Introduction: Various Human papillomavirus (HPV) types cause cervical cancer, and represent the primary cause of cancer death in Africa and the second cause of most common cancers in Cameroon. Herein, we determined the prevalence of high-risk HPV types in women and associated cervical cytologic abnormalities in Yaounde, Cameroon. Methodology: A cross-sectional study targeting HPV-positive women aged 20 and over was conducted between March and June 2020 at the Saint Martin de Porres’ Health Centre in Yaounde. HPV tests were performed by PCR for detection of HPVs 16, 18, 33, and 45. The test was performed on 616 women using exfoliated cell specimens; then, we processed on cytological diagnosis with Pap smears on HPV positive specimens. Results: The HPV types tested were detected in 137 participants, of which 38.7% with multiple HPV infections, and the remaining part with single HPV infections of type HPV 16 (28.5%), HPV 18 (17.5%), HPV 33 (10.2%), and HPV 45 (5.1%). Cervical cytologic abnormalities were found in 69.34% of participants including: LSIL (49.63%), HSIL (15.32%), ASC-US (3.66%) and AGC (0.73%). Co-infections with HPV 16 and HPV 18 were significantly associated with HSIL (p = 0.001) lesions, while HPV 45 was more common in participants with normal cytology (p = 0.001). Cervical lesion occurrence was significantly associated with the number of sexual partners (p = 0.02) and history of oral contraceptive pill use (p = 0.001). Conclusions: Our results suggest that HPV 16 and 18 are predominant in Yaounde, and are associated with more severe precancerous lesions.

scholarly journals Gp135/podocalyxin and NHERF-2 participate in the formation of a preapical domain during polarization of MDCK cells

2005 ◽  
Vol 168 (2) ◽  
pp. 303-313 ◽  
Author(s):  
Doris Meder ◽  
Anna Shevchenko ◽  
Kai Simons ◽  
Joachim Füllekrug
Keyword(s):  
Free Surface ◽  
Apical Membrane ◽  
Mdck Cells ◽  
Single Cells ◽  
Basolateral Membrane ◽  
Pdz Domain ◽  
Binding Motif ◽  
Membrane Domains ◽  
Regulatory Factor ◽  
Pdz Protein

Epithelial polarization involves the segregation of apical and basolateral membrane domains, which are stabilized and maintained by tight junctions and membrane traffic. We report that unlike most apical and basolateral proteins in MDCK cells, which separate only after junctions have formed, the apical marker gp135 signifies an early level of polarized membrane organization established already in single cells. We identified gp135 as the dog orthologue of podocalyxin. With a series of domain mutants we show that the COOH-terminal PSD-95/Dlg/ZO-1 (PDZ)–binding motif is targeting podocalyxin to the free surface of single cells as well as to a subdomain of the terminally polarized apical membrane. This special localization of podocalyxin is shared by the cytoplasmic PDZ-protein Na+/H+ exchanger regulatory factor (NHERF)-2. Depleting podocalyxin by RNA interference caused defects in epithelial polarization. Together, our data suggest that podocalyxin and NHERF-2 function in epithelial polarization by contributing to an early apical scaffold based on PDZ domain-mediated interactions.

scholarly journals Multi-PDZ Domain Protein MUPP1 Is a Cellular Target for both Adenovirus E4-ORF1 and High-Risk Papillomavirus Type 18 E6 Oncoproteins

2000 ◽  
Vol 74 (20) ◽  
pp. 9680-9693 ◽  
Author(s):  
Siu Sylvia Lee ◽  
Britt Glaunsinger ◽  
Fiamma Mantovani ◽  
Lawrence Banks ◽  
Ronald T. Javier
Keyword(s):  
High Risk ◽  
Cellular Proliferation ◽  
Pdz Domain ◽  
Viral Proteins ◽  
Cellular Protein ◽  
Human Papillomaviruses ◽  
Binding Motif ◽  
Cellular Factor ◽  
Domain Protein ◽  
Hpv 18

ABSTRACT A general theme that has emerged from studies of DNA tumor viruses is that otherwise unrelated oncoproteins encoded by these viruses often target the same important cellular factors. Major oncogenic determinants for human adenovirus type 9 (Ad9) and high-risk human papillomaviruses (HPV) are the E4-ORF1 and E6 oncoproteins, respectively, and although otherwise unrelated, both of these viral proteins possess a functional PDZ domain-binding motif that is essential for their transforming activity and for binding to the PDZ domain-containing and putative tumor suppressor protein DLG. We report here that the PDZ domain-binding motifs of Ad9 E4-ORF1 and high-risk HPV-18 E6 also mediate binding to the widely expressed cellular factor MUPP1, a large multi-PDZ domain protein predicted to function as an adapter in signal transduction. With regard to the consequences of these interactions in cells, we showed that Ad9 E4-ORF1 aberrantly sequesters MUPP1 within the cytoplasm of cells whereas HPV-18 E6 targets this cellular protein for degradation. These effects were specific because mutant viral proteins unable to bind MUPP1 lack these activities. From these results, we propose that the multi-PDZ domain protein MUPP1 is involved in negatively regulating cellular proliferation and that the transforming activities of two different viral oncoproteins depend, in part, on their ability to inactivate this cellular factor.

scholarly journals Human Papillomavirus Type 18 E6 Protein Binds the Cellular PDZ Protein TIP-2/GIPC, Which Is Involved in Transforming Growth Factor β Signaling and Triggers Its Degradation by the Proteasome

2005 ◽  
Vol 79 (7) ◽  
pp. 4229-4237 ◽  
Author(s):  
Arnaud Favre-Bonvin ◽  
Caroline Reynaud ◽  
Carole Kretz-Remy ◽  
Pierre Jalinot
Keyword(s):  
Human Papillomavirus ◽  
Growth Factor ◽  
Hela Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
Pdz Protein ◽  
E6 Protein ◽  
Hpv 18

ABSTRACT Several viral proteins expressed by DNA or RNA transforming viruses have the particular property of binding via their C-terminal end to various cellular proteins with PDZ domains. This study is focused on the PDZ protein TIP-2/GIPC, which was originally identified in two-hybrid screens performed with two different baits: the human T-cell leukemia virus type 1 Tax oncoprotein and the regulator of G signaling RGS-GAIP. Further studies have shown that TIP-2/GIPC is also able to associate with the cytoplasmic domains of various transmembrane proteins. In this report we show that TIP-2/GIPC interacts with the E6 protein of human papillomavirus type 18 (HPV-18). This event triggers polyubiquitination and proteasome-mediated degradation of the cellular protein. In agreement with this observation, silencing of E6 by RNA interference in HeLa cells causes an increase in the intracellular TIP-2/GIPC level. This PDZ protein has been previously found to be involved in transforming growth factor β (TGF-β) signaling by favoring expression of the TGF-β type III receptor at the cell membrane. In line with this activity of TIP-2/GIPC, we observed that depletion of this protein in HeLa cells hampers induction of the Id3 gene by TGF-β treatment and also diminishes the antiproliferative effect of this cytokine. Conversely, silencing of E6 increases the expression of Id3 and blocks proliferation of HeLa cells. These results support the notion that HPV-18 E6 renders cells less sensitive to the cytostatic effect of TGF-β by lowering the intracellular amount of TIP-2/GIPC.

scholarly journals Prevalence of Human Papillomavirus in Women from Mexico City

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
María Guadalupe López Rivera ◽  
Maria Olivia Medel Flores ◽  
José D’Artagnan Villalba Magdaleno ◽  
Virginia Sánchez Monroy
Keyword(s):  
Mexico City ◽  
High Frequency ◽  
Multiple Infections ◽  
Mexican Women ◽  
Genotype Distribution ◽  
Common Cancer ◽  
Random Samples ◽  
Hpv Genotypes ◽  
Hpv Types ◽  
Hpv 18

Introduction. Cervical cancer is the most common cancer among Mexican women. The goal of the present study was to determine the prevalence and distribution of HPV types in women from Mexico City.Methods. Our study was conducted in the Clinica de Especialidades de la Mujer de la Secretaría de la Defensa Nacional, Mexico. Random samples were taken from 929 healthy women requesting a cervical Papanicolaou examination. Detection and genotyping of HPV were performed by multiplex PCR, with the HPV4A ACE Screening kit (Seegene).Results. 85 of nine hundred twenty-nine women (9.1%) were infected with HPV. Of HPV-positive women, 99% and 1% had high- and low-risk HPV genotypes, respectively. The prevalence of the 16 high-risk (HR) HPV types that were screened was 43% : 42% (18) were HPV positive and 14% (16) were HPV positive, which includes coinfection. Multiple infections with different viral genotypes were detected in 10% of the positive cases. Abnormal cervical cytological results were found in only 15.3% of HPV-positive women, while 84.7% had normal cytological results.Conclusions. We found a similar prevalence of HPV to previous studies in Mexico. The heterogeneity of the HPV genotype distribution in Mexico is evident in this study, which found a high frequency of HPV HR genotypes, the majority of which were HPV 18.

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