scholarly journals Human Papillomavirus 16 (HPV-16), HPV-18, and HPV-31 E6 Override the Normal Phosphoregulation of E6AP Enzymatic Activity

2017 ◽  
Vol 91 (22) ◽  
Author(s):  
Jayashree Thatte ◽  
Lawrence Banks
Keyword(s):  
Human Papillomavirus ◽  
Enzymatic Activity ◽  
Ubiquitin Ligase ◽  
Subcellular Distribution ◽  
Hpv 16 ◽  
Human Papillomavirus 16 ◽  
Hpv E6 ◽  
Ubiquitin Ligase Activity ◽  
Hpv 18 ◽  
Stimulation Of

ABSTRACT The human papillomavirus (HPV) E6 oncoproteins recruit the cellular ubiquitin ligase E6AP/UBE3A to target cellular substrates for proteasome-mediated degradation, and one consequence of this activity is the E6 stimulation of E6AP autoubiquitination and degradation. Recent studies identified an autism-linked mutation within E6AP at T485, which was identified as a protein kinase A phosphoacceptor site and which could directly regulate E6AP ubiquitin ligase activity. In this study, we have analyzed how T485-mediated regulation of E6AP might affect E6 targeting of some of its known substrates. We show that modulation of T485 has no effect on the ability of E6 to direct either p53 or Dlg for degradation. Furthermore, T485 regulation has no effect on HPV-16 or HPV-31 E6-induced autodegradation of E6AP but does affect HPV-18 E6-induced autodegradation of E6AP. In cells derived from cervical cancers, we find low levels of both phosphorylated and nonphosphorylated E6AP in the nucleus. However, ablation of E6 results in a dramatic accumulation of phospho-E6AP in the cytoplasm, whereas nonphosphorylated E6AP accumulates primarily in the nucleus. Interestingly, E6AP phosphorylation at T485 confers association with 14-3-3 proteins, and this interaction seems to be important, in part, for the ability of E6 to recruit phospho-E6AP into the nucleus. These results demonstrate that HPV E6 overrides the normal phosphoregulation of E6AP, both in terms of its enzymatic activity and its subcellular distribution. IMPORTANCE Recent reports demonstrate the importance of phosphoregulation of E6AP for its normal enzymatic activity. Here, we show that HPV E6 is capable of overriding this regulation and can promote degradation of p53 and Dlg regardless of the phosphorylation status of E6AP. Furthermore, E6 interaction with E6AP also significantly alters how E6AP is subject to autodegradation and suggests that this is not a simple stimulation of an already-existing activity but rather a redirection of E6AP activity toward itself. Furthermore, E6-mediated regulation of the subcellular distribution of phospho-E6AP appears to be dependent, in part, upon the 14-3-3 family of proteins.

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 Acquisition and Persistence of Human Papillomavirus 16 (HPV-16) and HPV-18 Among Men With High-HPV Viral Load Infections in a Circumcision Trial in Kisumu, Kenya

2014 ◽  
Vol 211 (5) ◽  
pp. 811-820 ◽  
Author(s):  
Virginia Senkomago ◽  
Danielle M. Backes ◽  
Michael G. Hudgens ◽  
Charles Poole ◽  
Kawango Agot ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Viral Load ◽  
Hpv 16 ◽  
Human Papillomavirus 16 ◽  
Hpv Viral Load ◽  
Hpv 18

Human papillomavirus (HPV) E6/E7 mRNA as a triage test after detection of HPV 16 and HPV 18 DNA

2013 ◽  
Vol 85 (6) ◽  
pp. 1063-1068 ◽  
Author(s):  
Sonia Perez Castro ◽  
Amparo Iñarrea Fernández ◽  
María José Lamas González ◽  
María Teresa Sarán Diez ◽  
Ana Cid Lama ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Hpv 16 ◽  
Hpv E6 ◽  
Hpv 18 ◽  
Triage Test

scholarly journals Regulation of O-Linked N-Acetyl Glucosamine Transferase (OGT) through E6 Stimulation of the Ubiquitin Ligase Activity of E6AP

2021 ◽  
Vol 22 (19) ◽  
pp. 10286
Author(s):  
Kangli Peng ◽  
Ruochuan Liu ◽  
Caiwei Jia ◽  
Yiyang Wang ◽  
Geon H. Jeong ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Ubiquitin Ligase ◽  
Hek293 Cells ◽  
Cellular Proteins ◽  
Cellular Processes ◽  
Endogenous Expression ◽  
Protein Ubiquitination ◽  
Ubiquitin Ligase Activity ◽  
E6 Protein ◽  
Stimulation Of

Glycosyltransferase OGT catalyzes the conjugation of O-linked β-D-N-acetylglucosamine (O-GlcNAc) to Ser and Thr residues of the cellular proteins and regulates many key processes in the cell. Here, we report the identification of OGT as a ubiquitination target of HECT-type E3 ubiquitin (UB) ligase E6AP, whose overexpression in HEK293 cells would induce the degradation of OGT. We also found that the expression of E6AP in HeLa cells with the endogenous expression of the E6 protein of the human papillomavirus (HPV) would accelerate OGT degradation by the proteasome and suppress O-GlcNAc modification of OGT substrates in the cell. Overall, our study establishes a new mechanism of OGT regulation by the ubiquitin­–proteasome system (UPS) that mediates the crosstalk between protein ubiquitination and O-GlcNAcylation pathways underlying diverse cellular processes.

scholarly journals Molecular detection of oncogenic subtypes of human papillomavirus (HPV) in a group of women in the Amazon region of Brazil

2020 ◽  
Vol 42 ◽  
pp. e50005
Author(s):  
Alessandra Silva e Silva ◽  
Cláudia Giuliano Bica ◽  
Aniúsca Vieira ◽  
Cleiton Fantin
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Genetic Material ◽  
Hpv Infection ◽  
Cervical Cancer Prevention ◽  
Eligibility Criteria ◽  
Hpv 16 ◽  
Hpv Dna ◽  
Human Papillomavirus 16 ◽  
Hpv 18

The natural history of cervical cancer is strongly related to the presence of human papillomavirus (HPV) infection, with its relationship with cervical cancer being a matter of concern. It is estimated that 70% of all cervical cancers worldwide are caused by HPV 16 and 18. Accordingly, the present study aimed to contribute to the identification of HPV subtypes circulating in a group of women of Manaus-Brazil.  Cervical samples were collected from 49 women, following the eligibility criteria of the study, and DNA was then extracted from the samples, which were analyzed for the presence of the virus in the genetic material through the polymerase chain reaction (PCR) using generic primers (GP05/06). Finally, identification of the viral subtypes was performed using specific primers for the detection of the main subtypes already examined (16 and 18). Positive HPV DNA was detected in 100% of the samples included in the study. Human papillomavirus 16 was the most prevalent subtype in the majority of lesions, accounting for 29 (59.2%) of the positive cases, and HPV 18 was detected in four (8.2%) women. In these 4 cases there was co-infection, with the presence of both HPV 18 and HPV 16. Therefore, 40.8% (20 cases) in which HPV DNA was detected presented infection with other subtypes of HPV not included in the study. This data has clinical implications related to cervical cancer prevention, as the current prophylactic HPV vaccines are only effective against high-risk HPV 16 and 18 subtypes.

scholarly journals PDZ Domain-Containing Protein NHERF-2 Is a Novel Target of Human Papillomavirus 16 (HPV-16) and HPV-18

2019 ◽  
Vol 94 (1) ◽  
Author(s):  
Nathaniel Edward Bennett Saidu ◽  
Vedrana Filić ◽  
Miranda Thomas ◽  
Vanessa Sarabia-Vega ◽  
Anamaria Đukić ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Human Papillomavirus ◽  
Tumor Suppressor ◽  
Cyclin D1 ◽  
Cellular Proliferation ◽  
Pdz Domain ◽  
Hpv 16 ◽  
Hpv E6 ◽  
Endothelial Proliferation ◽  
Hpv 18

ABSTRACT Cancer-causing human papillomavirus (HPV) E6 oncoproteins have a class I PDZ-binding motif (PBM) on their C termini, which play critical roles that are related to the HPV life cycle and HPV-induced malignancies. E6 oncoproteins use these PBMs to interact with, to target for proteasome-mediated degradation, a plethora of cellular substrates that contain PDZ domains and that are involved in the regulation of various cellular pathways. In this study, we show that both HPV-16 and HPV-18 E6 oncoproteins can interact with Na+/H+ exchange regulatory factor 2 (NHERF-2), a PDZ domain-containing protein, which among other cellular functions also behaves as a tumor suppressor regulating endothelial proliferation. The interaction between the E6 oncoproteins and NHERF-2 is PBM dependent and results in proteasome-mediated degradation of NHERF-2. We further confirmed this effect in cells derived from HPV-16- and HPV-18-positive cervical tumors, where we show that NHERF-2 protein turnover is increased in the presence of E6. Finally, our data indicate that E6-mediated NHERF-2 degradation results in p27 downregulation and cyclin D1 upregulation, leading to accelerated cellular proliferation. To our knowledge, this is the first report to demonstrate that E6 oncoproteins can stimulate cell proliferation by indirectly regulating p27 through targeting a PDZ domain-containing protein. IMPORTANCE This study links HPV-16 and HPV-18 E6 oncoproteins to the modulation of cellular proliferation. The PDZ domain-containing protein NHERF-2 is a tumor suppressor that has been shown to regulate endothelial proliferation; here, we demonstrate that NHERF-2 is targeted by HPV E6 for proteasome-mediated degradation. Interestingly, this indirectly affects p27, cyclin D1, and CDK4 protein levels and, consequently, affects cell proliferation. Hence, this study provides information that will improve our understanding of the molecular basis for HPV E6 function, and it also highlights the importance of the PDZ domain-containing protein NHERF-2 and its tumor-suppressive role in regulating cell proliferation.

scholarly journals Incidence and Clearance of Anal Human Papillomavirus (HPV)-16 and HPV-18 Infection, and Their Determinants, Among Human Immunodeficiency Virus-Infected Men Who Have Sex With Men in France

2019 ◽  
Vol 221 (9) ◽  
pp. 1488-1493 ◽  
Author(s):  
Catharina J Alberts ◽  
Isabelle Heard ◽  
Ana Canestri ◽  
Lucie Marchand ◽  
Jean-François Fléjou ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Papillomavirus ◽  
Hpv Infection ◽  
High Grade ◽  
Hpv 16 ◽  
Human Papillomavirus 16 ◽  
Immunodeficiency Virus ◽  
Adjusted Incidence Rate ◽  
Sex With Men ◽  
Hpv 18

Abstract Background Prospective data on the natural history of anal human papillomavirus (HPV) infection are scarce in human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). Methods We analyzed incidence and clearance of HPV-16 and HPV-18 in a French cohort of HIV-infected MSM, aged ≥35 years, followed-up annually (n = 438, 2014–2018). Results Human papillomavirus-16 and HPV-18 incidence were similar (~10% incident infections at 24 months). Human papillomavirus-16 incidence was higher among high-grade versus no lesion at baseline (adjusted incidence rate ratio = 3.0; 95% confidence interval, 1.07–8.18). Human papillomavirus-16 cleared significantly slower than HPV-18 (32% versus 54% by 24 months). Conclusions In conclusion, anal HPV-16 is more persistent than HPV-18, and its incidence correlates with a prior detection of high-grade lesions.

scholarly journals Human Papillomavirus 16 (HPV 16) and HPV 18 Antibody Responses Measured by Pseudovirus Neutralization and Competitive Luminex Assays in a Two- versus Three-Dose HPV Vaccine Trial

2011 ◽  
Vol 18 (3) ◽  
pp. 418-423 ◽  
Author(s):  
Mel Krajden ◽  
Darrel Cook ◽  
Amanda Yu ◽  
Ron Chow ◽  
Wendy Mei ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Hpv Vaccine ◽  
Antibody Responses ◽  
Hpv 16 ◽  
Suitable Alternative ◽  
Human Papillomavirus 16 ◽  
Group 3 ◽  
Group 2 ◽  
Hpv 18 ◽  
Group 1

ABSTRACTHuman papillomavirus 16 (HPV 16) and HPV 18 antibody responses in a 2- versus 3-dose HPV vaccine (Gardasil) trial were measured by a pseudovirus neutralizing antibody (PsV NAb) assay and by the Merck competitive Luminex immunoassay (cLIA). Eight hundred twenty-four female subjects assigned to three dosing regimens (group 1, 9 to 13 years old; 2 doses, months 0 and 6 [n= 259]; group 2, 9 to 13 years old; 3 doses, months 0, 2, and 6 [n= 260]; group 3, 16 to 26 years old; 3 doses, months 0, 2, and 6 [n= 305]) had postvaccine responses assessed 1 month after the last dose. Of 791 subjects with baseline and 7-month sera, 15 (1.9%) and 9 (1.1%) were baseline seropositive for HPV 16 and HPV 18, respectively. All baseline-seronegative vaccinees seroconverted to both HPV 16 and HPV 18. Mean anti-HPV 16 levels were similar for groups 1 and 2 (for PsV NAb,P= 0.675; for cLIA,P= 0.874), and levels for both groups 1 and 2 were approximately 2-fold higher than that for group 3 (for PsV NAb and cLIA,P< 0.001). Mean anti-HPV 18 levels were approximately 1.4-fold lower in group 1 than in group 2 (for PsV, NAbP= 0.013; for cLIA,P= 0.001), and levels for both groups 1 and 2 were approximately 2.0- to 2.5-fold higher than that for group 3 (for PsV NAb and cLIA,P< 0.001). Pearson correlation coefficients for the assays were 0.672 for HPV 16 and 0.905 for HPV 18. Most of the discordant results were observed at lower cLIA signals. These results suggest that the PsV NAb assay could be a suitable alternative to cLIA for the measurement of postvaccine antibody responses.

scholarly journals DETEKSI INFEKSI Human papillomavirus (HPV) 16/18 PADA KARSINOMA SEL SKUAMOSA RONGGA MULUT DENGAN NESTED PCR

2019 ◽  
Author(s):  
Siti Hamidatul Aliyah
Keyword(s):  
Head And Neck Cancer ◽  
Human Papillomavirus ◽  
Head And Neck ◽  
Neck Cancer ◽  
Cancer Incidence ◽  
Nested Pcr ◽  
Hpv Infection ◽  
Hpv 16 ◽  
Hpv E6 ◽  
Hpv 18

Head and neck cancer ranks fourth nationally cancer incidence in Indonesia. Oral SCC isone of Head and neck cancer incidence. Oral SCCrelated to several factors, includingsmoking, alcohol, viral infection human papillomavirus (HPV 16/18) and genetic On theother hand, HPV E6 oncoprotein binds and inactivates TP53, and result in loss of control ofthe cell cycle.This study aimed to detect HPV 16/18 infection in oral SCC. Detection of HPVserotypes 16 and 18 performed on FFPE DNA isolates oral SCC with the method of nestedPolymerase Chain Reaction (PCR). Nested PCR was performed in two stages, namelyamplification with L1 primer, followed by specific PCR E6 HPV-16 and HPV-18. A total of33% (11/33) FFPE samples showed positive for HPV 18 infection (single-sized DNA bands415bp) and not detected the presence of infection with HPV 16. It can be concluded that thetype of FFPE biosampel can be used for studies related to HPV infection. Furthermore, itshould be tested on different types biosampel by a larger amount so as to represent theprevalence of oncogenic HPV infection in Indonesia.

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