35 research outputs found
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The Role of the Ubiquitin Proteasome Pathway in Papillomavirus Pathogenicity
To establish an infection in the host cell, Papillomaviruses (PVs) encode two major oncoproteins, E6 and E7, which interact with numerous cellular proteins and interfere with many cellular pathways. We use HPV E6 and RhPV-1 E7 oncoproteins as tools to investigate some of the most important characteristics of the high-risk HPV E6 proteins: their association with the ubiquitin pathway and ability to direct proteasomal degradation of PDZ domain-containing proteins. We show that E6 protein levels are dependent on the E6AP ubiquitin ligase: in its absence, E6 is degraded in a proteasome dependent manner. A proteomic analysis for HPV-18 E6 interacting partners showed that HPV-18 E6 interacts with EDD, another HECT domain ubiquitin ligase. EDD does not direct the degradation of p53 or PDZ domain-containing substrates, but appears to regulate E6AP levels, with consequent effects on E6 protein levels and its p53 targeting. These studies demonstrate a complex interplay between E6, EDD and E6AP for regulating E6ās degradation of its substrate proteins. Rhesus papillomavirus 1 (RhPV-1) is a high-risk mucosal papillomavirus, but its E6 protein has no PDZ-binding motif. However, we show a remarkable evolutionary conservation, with the PDZ-binding motif present on the RhPV-1 E7 protein instead. Furthermore, this directs the binding of RhPV-1 E7 to Par3, a PDZ domain-containing protein controlling the polarity regulation pathway also controlled by hDlg and hScrib, the PDZ domain-containing targets of HPV-18 and HPV-16 E6. RhPV-1 E7 degrades Par3 analogously to HPV E6ās degradation of its PDZ substrates, and also appears to interact with EDD. These studies demonstrate that PDZ domain-containing cell polarity regulators and critical components of the ubiquitin proteasome pathway are common targets of evolutionarily diverse oncogenic mucosal papillomaviruses. This suggests that these pathways represent essential steps in the viral life cycles and in these virusesā ability to induce malignancy
Functional Roles of E6 and E7 Oncoproteins in HPV-Induced Malignancies at Diverse Anatomical Sites
Approximately 200 human papillomaviruses (HPVs) infect human epithelial cells, of which the alpha and beta types have been the most extensively studied. Alpha HPV types mainly infect mucosal epithelia and a small group of these causes over 600, 000 cancers per year worldwide at various anatomical sites, especially anogenital and head-and-neck cancers. Of these the most important is cervical cancer, which is the leading cause of cancer-related death in women in many parts of the world. Beta HPV types infect cutaneous epithelia and may contribute towards the initiation of non- melanoma skin cancers. HPVs encode two oncoproteins, E6 and E7, which are directly responsible for the development of HPV-induced carcinogenesis. They do this cooperatively by targeting diverse cellular pathways involved in the regulation of cell cycle control, of apoptosis and of cell polarity control networks. In this review, the biological consequences of papillomavirus targeting of various cellular substrates at diverse anatomical sites in the development of HPV-induced malignancies are highlighted
Do or Die: HPV E5, E6 and E7 in Cell Death Evasion
Abstract: Human papillomaviruses (HPVs) infect the dividing cells of human epithelia and hijack the cellular replication machinery to ensure their own propagation. In the effort to adapt the cell to suit their own reproductive needs, the virus changes a number of processes, amongst which is the ability of the cell to undergo programmed cell death. Viral infections, forced cell divisions and mutations, which accumulate as a result of uncontrolled proliferation, all trigger one of several cell death pathways. Here, we examine the mechanisms employed by HPVs to ensure the survival of infected cells manipulated into cell cycle progression and proliferation
Interaction of HPV E6 oncoproteins with specific proteasomal subunits
AbstractThe Human Papillomavirus E6 oncoproteins have the capacity to target several of their cellular interacting partners for proteasome mediated degradation, and recent proteomic analyses suggest a close involvement of E6 with the cellular proteasome machinery. In this study we have performed an extensive analysis of the capacity of different E6 oncoproteins to interact with specific proteasome components. We demonstrate that multiple subunits of the proteasome can be bound by different HPV E6 oncoproteins. Furthermore, whilst most of these interactions appear independent of the E6AP ubiquitin ligase, the association of E6 with the major ubiquitin-accepting proteasome subunit, S5a, does require the presence of E6AP. One consequence of the interaction between E6/E6AP and S5a is enhanced ubiquitination of this proteasome subunit. These results suggest a complex interplay between E6 and the proteasome, only some aspects of which are dependent upon the E6AP ubiquitin ligase
EpigenetiÄki biljezi u tumorima glave i vrata: posebni osvrt na tumore orofarinksa povezane s HPV-om
UnatoÄ kontinuiranim naporima da se identificiraju molekularni biljezi za rano otkrivanje tumora glave i vrata (engl. HNC, head and neck cancer) te poboljÅ”anoj terapiji, ukupno preživljenje i prognoza bolesnika s HNC-om i dalje su loÅ”i. Znanstveni dokazi sugeriraju da tumori povezani s HPV-om imaju bolju prognozu i preživljenje. Nadalje, epigenetiÄke promjene su opÄenito Äesto ukljuÄene u karcinogenezu, napredovanje tumora glave i vrata te rezistenciju na terapiju. Stoga razumijevanje i karakterizacija epigenetiÄkih modifikacija povezanih s karcinogenezom tumora glave i vrata obeÄavaju identifikaciju epigenetiÄkih biljega za rano otkrivanje raka i poboljÅ”anje terapijskih pristupa u borbi protiv raka. U ovom preglednom radu dan je osvrt na trenutno znanje o epigenetiÄkim modifikacijama, odnosno metiliranju DNA i mikroRNA uoÄenim kod HNC-a, posebno kod tumora orofarinksa pozitivnih na HPV
HPV-associated oncogenesis in head and neck cancer
ViÅ”e od 200 papilomavirusa Äovjeka (HPV) inficira stanice ljudskog epitela, od kojih su alfa i beta tipovi najopsežnije prouÄavani i analizirani. Alfa-tipovi HPV-a primarno inficiraju epitel sluznice, a samo manji njihov dio povezan je s viÅ”e od 600.000 karcinoma godiÅ”nje Å”irom svijeta na razliÄitim anatomskim mjestima, posebno anogenitalnim i regijama glave i vrata. Najvažniji karcinom uzrokovan alfa-tipovima HPV-a jest rak vrata maternice, koji je vodeÄi uzrok smrti povezane s rakom kod žena u mnogim dijelovima svijeta. HPV kodiraju dva onkoproteina, E6 i E7, koji izravno sudjeluju u razvoju malignosti povezanih s HPV-om. Oni djeluju u sinergiji, ciljajuÄi razliÄite staniÄne puteve koji su ukljuÄeni u regulaciju kontrole staniÄnog ciklusa, apoptoze i polariteta stanica. U ovom su pregledu istaknute bioloÅ”ke posljedice papilomavirusa koji djeluju na razliÄite staniÄne proteine na razliÄitim anatomskim mjestima u razvoju malignih tumora izazvanih HPV-om, s naglaskom na tumore glave i vrataMore than 200 human papillomaviruses (HPVs) infect human epithelial cells, and out of them alpha and beta types have been the most extensively investigated and analysed. Alpha HPVs primarily infect mucosal epithelia and only a small proportion of them is associated with more than 600,000 cancers per year worldwide at various anatomical sites, especially anogenital and head-and-neck region. Of these the central disease is cervical cancer, which is the leading cause of cancer-related deaths in women in numerous parts of the world. HPVs encode two oncoproteins, E6 and E7, which are directly involved in the development of HPV-mediated malignancies. They do this in cooperation by targeting various cellular pathways involved in the regulation of cell cycle control, of apoptosis and of cell polarity control networks. In this review, the biological consequences of HPV manipulating of various cellular proteins at diverse anatomical sites in the development of HPV-induced carcinogenesis are depicted, with focus on head and neck cancer
Cancer-causing human papillomavirus E6 proteins display major differences in the phospho-regulation of their PDZ interactions
Previous 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. IMPORTANCE This 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
Human DLG1 and SCRIB are distinctly regulated independently of HPV-16 during the progression of oropharyngeal squamous cell carcinomas: a preliminary analysis
The major causative agents of head and neck squamous cell carcinomas (HNSCCs) are either environmental factors, such as tobacco and alcohol consumption, or infection with oncogenic human papillomaviruses (HPVs). An important aspect of HPV-induced oncogenesis is the targeting by the E6 oncoprotein of PDZ domain-containing substrates for proteasomal destruction. Tumor suppressors DLG1 and SCRIB are two of the principal PDZ domain-containing E6 targets. Both have been shown to play critical roles in the regulation of cell growth and polarity and in maintaining the structural integrity of the epithelia. We investigated how modifications in the cellular localization and protein expression of DLG1 and SCRIB in HPV16- positive and HPV-negative histologic oropharyngeal squamous cell carcinomas (OPSCC) might reflect disease progression. HPV presence was determined by p16 staining and HPV genotyping. Whilst DLG1 expression levels did not differ markedly between HPV-negative and HPV16-positive OPSCCs, it appeared to be relocated from cellācell contacts to the cytoplasm in most samples, regardless of HPV16 positivity. This indicates that alterations in DLG1 distribution could contribute to malignant progression in OPSCCs. Interestingly, SCRIB was also relocated from cellācell contacts to the cytoplasm in the tumor samples in comparison with normal tissue, regardless of HPV16 status, but in addition there was an obvious reduction in SCRIB expression in higher grade tumors. Strikingly, loss of SCRIB was even more pronounced in HPV16-positive OPSCCs. These alterations in SCRIB levels may contribute to transformation and loss of tissue architecture in the process of carcinogenesis and could potentially serve as markers in the development of OPSCCs
Interaction of the Human Papillomavirus E6 Oncoprotein with Sorting Nexin 27 Modulates Endocytic Cargo Transport Pathways
A subset of high-risk Human Papillomaviruses (HPVs) are the causative agents of a large number of human cancers, of which cervical is the most common. Two viral oncoproteins, E6 and E7, contribute directly towards the development and maintenance of malignancy. A characteristic feature of the E6 oncoproteins from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at its C-terminus, which confers interaction with cellular proteins harbouring PDZ domains. Here we show that this motif allows E6 interaction with Sorting Nexin 27 (SNX27), an essential component of endosomal recycling pathways. This interaction is highly conserved across E6 proteins from multiple high-risk HPV types and is mediated by a classical PBM-PDZ interaction but unlike many E6 targets, SNX27 is not targeted for degradation by E6. Rather, in HPV-18 positive cell lines the association of SNX27 with components of the retromer complex and the endocytic transport machinery is altered in an E6 PBM-dependent manner. Analysis of a SNX27 cargo, the glucose transporter GLUT1, reveals an E6-dependent maintenance of GLUT1 expression and alteration in its association with components of the endocytic transport machinery. Furthermore, knockdown of E6 in HPV-18 positive cervical cancer cells phenocopies the loss of SNX27, both in terms of GLUT1 expression levels and its vesicular localization, with a concomitant marked reduction in glucose uptake, whilst loss of SNX27 results in slower cell proliferation in low nutrient conditions. These results demonstrate that E6 interaction with SNX27 can alter the recycling of cargo molecules, one consequence of which is modulation of nutrient availability in HPV transformed tumour cells