Autism and Human Papillomavirus (HPV) E6: A Comprehensive Review
Abstract
Objective: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication impairments, restricted interests, and repetitive behaviors. The etiology of ASD is complex, involving genetic and environmental factors. The HECT (Homologous to the E6-AP Carboxyl Terminus) family protein E6-associated protein (E6-AP), encoded by the UBE3A gene, is an ubiquitin ligase implicated in neurological disorders, including Angelman syndrome (AS) and potentially ASD. Dysregulation of E6-AP, influenced by environmental factors such as human papillomavirus (HPV) E6 protein, may contribute to neurodevelopmental abnormalities.
Method: This review synthesizes current literature to explore the potential link between HPV E6 protein and E6-AP dysfunction in the context of ASD. We analyzed 32 peer-reviewed studies, including 12 original research articles, 10 reviews, and 10 meta-analyses, retrieved from PubMed and Google Scholar, focusing on E6-AP’s roles in ubiquitin-mediated signaling pathways, its dysregulation in neurodevelopmental disorders, and the impact of HPV E6 on E6-AP function.
Results: E6-AP is critical in regulating signaling pathways associated with tumorigenesis and neurodevelopment. Dysregulation of E6-AP, potentially induced by HPV E6, has been implicated in AS and, to a lesser extent, ASD. As visually demonstrated in Figure 1, these complex relationships between HPV, neurodevelopmental disorders, and E6 protein underscore the need for cross-disciplinary research. Current findings indicate that HPV E6 may disrupt E6-AP’s ubiquitin ligase activity, potentially contributing to neurodevelopmental impairments observed in ASD.
Conclusion: The potential link between HPV E6 and E6-AP dysfunction underscores a novel avenue for understanding environmental contributors to ASD. Given the complexity of ASD, further research is essential to elucidate E6-AP’s role and to develop targeted therapeutic strategies. This review highlights the need for studies investigating HPV-related mechanisms in ASD to advance effective interventions and support systems.
1. Yeo-Teh NSL, Ito Y, Jha S. High-Risk Human Papillomaviral Oncogenes E6 and E7 Target Key Cellular Pathways to Achieve Oncogenesis. Int J Mol Sci. 2018;19(6):1706.
2. Owais A, Mishra RK, Kiyokawa H. The HECT E3 Ligase E6AP/UBE3A as a Therapeutic Target in Cancer and Neurological Disorders. Cancers (Basel). 2020;12(8):2108.
3. Li S, Hong X, Wei Z, Xie M, Li W, Liu G, et al. Ubiquitination of the HPV Oncoprotein E6 Is Critical for E6/E6AP-Mediated p53 Degradation. Front Microbiol. 2019;10:2483.
4. Martínez-Noël G, Galligan JT, Sowa ME, Arndt V, Overton TM, Harper JW, et al. Identification and proteomic analysis of distinct UBE3A/E6AP protein complexes. Mol Cell Biol. 2012;32(15):3095–106.
5. Drews CM, Brimer N, Vande Pol SB. Multiple regions of E6AP (UBE3A) contribute to interaction with papillomavirus E6 proteins and the activation of ubiquitin ligase activity. PLoS Pathog. 2020;16(1):e1008295.
6. Mortensen F, Schneider D, Barbic T, Sladewska-Marquardt A, Kühnle S, Marx A, et al. Role of ubiquitin and the HPV E6 oncoprotein in E6AP-mediated ubiquitination. Proc Natl Acad Sci U S A. 2015;112(32):9872–7.
7. Ahmad A, Ansari IA. A Comprehensive Review on Cross-talk of Human Papilloma Virus Oncoproteins and Developmental/Self-Renewal Pathways During the Pathogenesis of Uterine Cervical Cancer. Curr Mol Med. 2021;21(5):402–16.
8. Hakanen J. Molecular regulation of forebrain development and neural stem/progenitor cells. 2014.
9. Khatri N, Man HY. The Autism and Angelman Syndrome Protein Ube3A/E6AP: The Gene, E3 Ligase Ubiquitination Targets and Neurobiological Functions. Front Mol Neurosci. 2019;12:109.
10. Mohammadi MR, Ahmadi N, Khaleghi A, Zarafshan H, Mostafavi SA, Kamali K, et al. Prevalence of Autism and its Comorbidities and the Relationship with Maternal Psychopathology: A National Population-Based Study. Arch Iran Med. 2019;22(10):546–53.
11. Martínez-Noël G, Luck K, Kühnle S, Desbuleux A, Szajner P, Galligan JT, et al. Network Analysis of UBE3A/E6AP-Associated Proteins Provides Connections to Several Distinct Cellular Processes. J Mol Biol. 2018;430(7):1024–50.
12. Kühnle S, Mothes B, Matentzoglu K, Scheffner M. Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc. Proc Natl Acad Sci U S A. 2013;110(22):8888–93.
13. Roy B, Amemasor E, Hussain S, Castro K. UBE3A: The Role in Autism Spectrum Disorders (ASDs) and a Potential Candidate for Biomarker Studies and Designing Therapeutic Strategies. Diseases. 2023;12(1):7.
14. Ramos-Martínez IE, Ramos-Martínez E, Segura-Velázquez R, Saavedra-Montañez M, Cervantes-Torres JB, Cerbón M, et al. Heparan Sulfate and Sialic Acid in Viral Attachment: Two Sides of the Same Coin? Int J Mol Sci. 2022;23(17):9842.
15. Gentile I, Zappulo E, Militerni R, Pascotto A, Borgia G, Bravaccio C. Etiopathogenesis of autism spectrum disorders: fitting the pieces of the puzzle together. Med Hypotheses. 2013;81(1):26–35.
16. Ganguli S, Chavali PL. Intrauterine Viral Infections: Impact of Inflammation on Fetal Neurodevelopment. Front Neurosci. 2021;15:771557.
17. Wang Z, Fan F, Li Z, Ye F, Wang Q, Gao R, et al. Structural insights into the functional mechanism of the ubiquitin ligase E6AP. Nat Commun. 2024;15(1):3531.
18. Khatri N, Gilbert JP, Huo Y, Sharaflari R, Nee M, Qiao H, et al. The Autism Protein Ube3A/E6AP Remodels Neuronal Dendritic Arborization via Caspase-Dependent Microtubule Destabilization. J Neurosci. 2018;38(2):363–78.
19. Shuid AN, Jayusman PA, Shuid N, Ismail J, Kamal Nor N, Mohamed IN. Association between Viral Infections and Risk of Autistic Disorder: An Overview. Int J Environ Res Public Health. 2021;18(6):2817.
20. Estêvão D, Costa NR, Gil da Costa RM, Medeiros R. Hallmarks of HPV carcinogenesis: The role of E6, E7 and E5 oncoproteins in cellular malignancy. Biochim Biophys Acta Gene Regul Mech. 2019;1862(2):153–62.
21. Enriquez KD, Gupta AR, Hoffman EJ. Signaling Pathways and Sex Differential Processes in Autism Spectrum Disorder. Front Psychiatry. 2021;12:716673.
22. Hall HA, Speyer LG, Murray AL, Auyeung B. Prenatal Maternal Infections and Children's Neurodevelopment in the UK Millennium Cohort Study: A Focus on ASD and ADHD. J Atten Disord. 2022;26(4):616–28.
23. Jones EJ, Gliga T, Bedford R, Charman T, Johnson MH. Developmental pathways to autism: a review of prospective studies of infants at risk. Neurosci Biobehav Rev. 2014;39(100):1–33.
24. Lappé M, Lau L, Dudovitz RN, Nelson BB, Karp EA, Kuo AA. The Diagnostic Odyssey of Autism Spectrum Disorder. Pediatrics. 2018;141(Suppl 4):S272–s9.
25. Bhandari R, Paliwal JK, Kuhad A. Neuropsychopathology of Autism Spectrum Disorder: Complex Interplay of Genetic, Epigenetic, and Environmental Factors. Adv Neurobiol. 2020;24:97–141.
26. Raghavendra P, Pullaiah T. Advances in cell and molecular diagnostics: Academic Press; 2018.
27. Nielsen TC, Nassar N, Shand AW, Jones H, Guastella AJ, Dale RC, et al. Association of Maternal Autoimmune Disease With Attention-Deficit/Hyperactivity Disorder in Children. JAMA Pediatr. 2021;175(3):e205487.
28. Sealey LA, Hughes BW, Sriskanda AN, Guest JR, Gibson AD, Johnson-Williams L, et al. Environmental factors in the development of autism spectrum disorders. Environ Int. 2016;88:288–98.
29. Niyibizi J, Mayrand MH, Audibert F, Monnier P, Brassard P, Laporte L, et al. Association Between Human Papillomavirus Infection Among Pregnant Women and Preterm Birth. JAMA Netw Open. 2021;4(9):e2125308.
30. Kühnle S, Martínez-Noël G, Leclere F, Hayes SD, Harper JW, Howley PM. Angelman syndrome-associated point mutations in the Zn(2+)-binding N-terminal (AZUL) domain of UBE3A ubiquitin ligase inhibit binding to the proteasome. J Biol Chem. 2018;293(47):18387–99.
31. Matentzoglu K, Scheffner M. Ubiquitin ligase E6-AP and its role in human disease. Biochem Soc Trans. 2008;36(Pt 5):797–801.
32. Thatte J, Banks L. Human Papillomavirus 16 (HPV-16), HPV-18, and HPV-31 E6 Override the Normal Phosphoregulation of E6AP Enzymatic Activity. J Virol. 2017;91(22): e01390-17.
33. Kępińska AP, Iyegbe CO, Vernon AC, Yolken R, Murray RM, Pollak TA. Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic: Mechanisms of Psychosis Risk. Front Psychiatry. 2020;11:72.
34. Di Marco B, Bonaccorso CM, Aloisi E, D'Antoni S, Catania MV. Neuro-Inflammatory Mechanisms in Developmental Disorders Associated with Intellectual Disability and Autism Spectrum Disorder: A Neuro- Immune Perspective. CNS Neurol Disord Drug Targets. 2016;15(4):448–63.
35. Bonfim TA, Giacon-Arruda BCC, Hermes-Uliana C, Galera SAF, Marcheti MA. Family experiences in discovering Autism Spectrum Disorder: implications for family nursing. Rev Bras Enferm. 2020;73(s6):e20190489.
36. Hirota T, King BH. Autism Spectrum Disorder: A Review. Jama. 2023;329(2):157–68.
37. Eigbe IJ, Gamboa CM, Gjini J, Mukherjee J, Dube S. Gut Microbiome and Nutrition Interplay in Regulating and Improving Autism Spectrum Disorder Related Social Symptoms. 2024.
38. Nisticò V, Iacono A, Goeta D, Tedesco R, Giordano B, Faggioli R, et al. Hypermobile spectrum disorders symptoms in patients with functional neurological disorders and autism spectrum disorders: A preliminary study. Front Psychiatry. 2022;13:943098.
39. Patel M, Atluri LM, Gonzalez NA, Sakhamuri N, Athiyaman S, Randhi B, et al. A Systematic Review of Mixed Studies Exploring the Effects of Probiotics on Gut-Microbiome to Modulate Therapy in Children With Autism Spectrum Disorder. Cureus. 2022;14(12):e32313.
40. Wang JCK, Baddock HT, Mafi A, Foe IT, Bratkowski M, Lin TY, et al. Structure of the p53 degradation complex from HPV16. Nat Commun. 2024;15(1):1842.
41. Billingsley CL, Chintala S, Katzenellenbogen RA. Post-Transcriptional Gene Regulation by HPV 16E6 and Its Host Protein Partners. Viruses. 2022;14(7).
42. Shimada M, Yamashita A, Saito M, Ichino M, Kinjo T, Mizuki N, et al. The human papillomavirus E6 protein targets apoptosis-inducing factor (AIF) for degradation. Sci Rep. 2020;10(1):14195.
43. Trajkovski V. Association between Autism Spectrum Disorder and Cancer-a Review from the Literature. Journal of Health and Rehabilitation Sciences. 2024;3(1):21–7.
44. Squarzanti DF, Sorrentino R, Landini MM, Chiesa A, Pinato S, Rocchio F, et al. Human papillomavirus type 16 E6 and E7 oncoproteins interact with the nuclear p53-binding protein 1 in an in vitro reconstructed 3D epithelium: new insights for the virus-induced DNA damage response. Virol J. 2018;15(1):176.
45. Bordonaro M. Hypothesis: Cancer Is a Disease of Evolved Trade-Offs Between Neoplastic Virulence and Transmission. J Cancer. 2018;9(10):1707–24.
46. Chaudhary P, Proulx J, Park IW. Ubiquitin-protein ligase E3A (UBE3A) mediation of viral infection and human diseases. Virus Res. 2023;335:199191.
47. Peng K, Liu R, Jia C, Wang Y, Jeong GH, Zhou L, et al. Regulation of O-Linked N-Acetyl Glucosamine Transferase (OGT) through E6 Stimulation of the Ubiquitin Ligase Activity of E6AP. Int J Mol Sci. 2021;22(19):10286.
48. Buel GR, Chen X, Chari R, O'Neill MJ, Ebelle DL, Jenkins C, et al. Structure of E3 ligase E6AP with a proteasome-binding site provided by substrate receptor hRpn10. Nat Commun. 2020;11(1):1291.
49. Romero-Masters JC, Lambert PF, Munger K. Molecular Mechanisms of MmuPV1 E6 and E7 and Implications for Human Disease. Viruses. 2022;14(10):2138.
50. Meyer U, Feldon J, Yee BK. A review of the fetal brain cytokine imbalance hypothesis of schizophrenia. Schizophr Bull. 2009;35(5):959–72.
51. de Bakker T, Journe F, Descamps G, Saussez S, Dragan T, Ghanem G, et al. Restoring p53 Function in Head and Neck Squamous Cell Carcinoma to Improve Treatments. Front Oncol. 2021;11:799993.
52. Nabati F, Moradi M, Mohabatkar H. In silico analyzing the molecular interactions of plant-derived inhibitors against E6AP, p53, and c-Myc binding sites of HPV type 16 E6 oncoprotein. Mol Biol Res Commun. 2020;9(2):71–82.
53. Al-Beltagi M, Saeed NK, Elbeltagi R, Bediwy AS, Aftab SAS, Alhawamdeh R. Viruses and autism: A Bi-mutual cause and effect. World J Virol. 2023;12(3):172–92.
54. Mohammadi Manesh M, Mohebbi A, Yasaghi M, Najafi Memar Z, Javid N, Taziki SA, et al. Low Prevalence of Borna Disease Virus RNA in Patients with Bipolar Major Depression and Schizophrenia in North of Iran. Iran J Virol. 2017;11(2):8-13.
55. Hidayatullah A, Putra WE, Sustiprijatno S, RIFA’I M, Widiastuti D, Heikal MF, et al. Concatenation of molecular docking and dynamics simulation of human papillomavirus type 16 E7 oncoprotein targeted ligands: In quest of cervical cancer’s treatment. Anais da Academia Brasileira de Ciências. 2023;95(suppl 1):e20220633.
56. Pintacuda G, Martín JM, Eggan KC. Mind the translational gap: using iPS cell models to bridge from genetic discoveries to perturbed pathways and therapeutic targets. Mol Autism. 2021;12(1):10.
57. Hong D, Iakoucheva LM. Therapeutic strategies for autism: targeting three levels of the central dogma of molecular biology. Transl Psychiatry. 2023;13(1):58.
58. Mehta R, Kuhad A, Bhandari R. Nitric oxide pathway as a plausible therapeutic target in autism spectrum disorders. Expert Opin Ther Targets. 2022;26(7):659–79.
2. Owais A, Mishra RK, Kiyokawa H. The HECT E3 Ligase E6AP/UBE3A as a Therapeutic Target in Cancer and Neurological Disorders. Cancers (Basel). 2020;12(8):2108.
3. Li S, Hong X, Wei Z, Xie M, Li W, Liu G, et al. Ubiquitination of the HPV Oncoprotein E6 Is Critical for E6/E6AP-Mediated p53 Degradation. Front Microbiol. 2019;10:2483.
4. Martínez-Noël G, Galligan JT, Sowa ME, Arndt V, Overton TM, Harper JW, et al. Identification and proteomic analysis of distinct UBE3A/E6AP protein complexes. Mol Cell Biol. 2012;32(15):3095–106.
5. Drews CM, Brimer N, Vande Pol SB. Multiple regions of E6AP (UBE3A) contribute to interaction with papillomavirus E6 proteins and the activation of ubiquitin ligase activity. PLoS Pathog. 2020;16(1):e1008295.
6. Mortensen F, Schneider D, Barbic T, Sladewska-Marquardt A, Kühnle S, Marx A, et al. Role of ubiquitin and the HPV E6 oncoprotein in E6AP-mediated ubiquitination. Proc Natl Acad Sci U S A. 2015;112(32):9872–7.
7. Ahmad A, Ansari IA. A Comprehensive Review on Cross-talk of Human Papilloma Virus Oncoproteins and Developmental/Self-Renewal Pathways During the Pathogenesis of Uterine Cervical Cancer. Curr Mol Med. 2021;21(5):402–16.
8. Hakanen J. Molecular regulation of forebrain development and neural stem/progenitor cells. 2014.
9. Khatri N, Man HY. The Autism and Angelman Syndrome Protein Ube3A/E6AP: The Gene, E3 Ligase Ubiquitination Targets and Neurobiological Functions. Front Mol Neurosci. 2019;12:109.
10. Mohammadi MR, Ahmadi N, Khaleghi A, Zarafshan H, Mostafavi SA, Kamali K, et al. Prevalence of Autism and its Comorbidities and the Relationship with Maternal Psychopathology: A National Population-Based Study. Arch Iran Med. 2019;22(10):546–53.
11. Martínez-Noël G, Luck K, Kühnle S, Desbuleux A, Szajner P, Galligan JT, et al. Network Analysis of UBE3A/E6AP-Associated Proteins Provides Connections to Several Distinct Cellular Processes. J Mol Biol. 2018;430(7):1024–50.
12. Kühnle S, Mothes B, Matentzoglu K, Scheffner M. Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc. Proc Natl Acad Sci U S A. 2013;110(22):8888–93.
13. Roy B, Amemasor E, Hussain S, Castro K. UBE3A: The Role in Autism Spectrum Disorders (ASDs) and a Potential Candidate for Biomarker Studies and Designing Therapeutic Strategies. Diseases. 2023;12(1):7.
14. Ramos-Martínez IE, Ramos-Martínez E, Segura-Velázquez R, Saavedra-Montañez M, Cervantes-Torres JB, Cerbón M, et al. Heparan Sulfate and Sialic Acid in Viral Attachment: Two Sides of the Same Coin? Int J Mol Sci. 2022;23(17):9842.
15. Gentile I, Zappulo E, Militerni R, Pascotto A, Borgia G, Bravaccio C. Etiopathogenesis of autism spectrum disorders: fitting the pieces of the puzzle together. Med Hypotheses. 2013;81(1):26–35.
16. Ganguli S, Chavali PL. Intrauterine Viral Infections: Impact of Inflammation on Fetal Neurodevelopment. Front Neurosci. 2021;15:771557.
17. Wang Z, Fan F, Li Z, Ye F, Wang Q, Gao R, et al. Structural insights into the functional mechanism of the ubiquitin ligase E6AP. Nat Commun. 2024;15(1):3531.
18. Khatri N, Gilbert JP, Huo Y, Sharaflari R, Nee M, Qiao H, et al. The Autism Protein Ube3A/E6AP Remodels Neuronal Dendritic Arborization via Caspase-Dependent Microtubule Destabilization. J Neurosci. 2018;38(2):363–78.
19. Shuid AN, Jayusman PA, Shuid N, Ismail J, Kamal Nor N, Mohamed IN. Association between Viral Infections and Risk of Autistic Disorder: An Overview. Int J Environ Res Public Health. 2021;18(6):2817.
20. Estêvão D, Costa NR, Gil da Costa RM, Medeiros R. Hallmarks of HPV carcinogenesis: The role of E6, E7 and E5 oncoproteins in cellular malignancy. Biochim Biophys Acta Gene Regul Mech. 2019;1862(2):153–62.
21. Enriquez KD, Gupta AR, Hoffman EJ. Signaling Pathways and Sex Differential Processes in Autism Spectrum Disorder. Front Psychiatry. 2021;12:716673.
22. Hall HA, Speyer LG, Murray AL, Auyeung B. Prenatal Maternal Infections and Children's Neurodevelopment in the UK Millennium Cohort Study: A Focus on ASD and ADHD. J Atten Disord. 2022;26(4):616–28.
23. Jones EJ, Gliga T, Bedford R, Charman T, Johnson MH. Developmental pathways to autism: a review of prospective studies of infants at risk. Neurosci Biobehav Rev. 2014;39(100):1–33.
24. Lappé M, Lau L, Dudovitz RN, Nelson BB, Karp EA, Kuo AA. The Diagnostic Odyssey of Autism Spectrum Disorder. Pediatrics. 2018;141(Suppl 4):S272–s9.
25. Bhandari R, Paliwal JK, Kuhad A. Neuropsychopathology of Autism Spectrum Disorder: Complex Interplay of Genetic, Epigenetic, and Environmental Factors. Adv Neurobiol. 2020;24:97–141.
26. Raghavendra P, Pullaiah T. Advances in cell and molecular diagnostics: Academic Press; 2018.
27. Nielsen TC, Nassar N, Shand AW, Jones H, Guastella AJ, Dale RC, et al. Association of Maternal Autoimmune Disease With Attention-Deficit/Hyperactivity Disorder in Children. JAMA Pediatr. 2021;175(3):e205487.
28. Sealey LA, Hughes BW, Sriskanda AN, Guest JR, Gibson AD, Johnson-Williams L, et al. Environmental factors in the development of autism spectrum disorders. Environ Int. 2016;88:288–98.
29. Niyibizi J, Mayrand MH, Audibert F, Monnier P, Brassard P, Laporte L, et al. Association Between Human Papillomavirus Infection Among Pregnant Women and Preterm Birth. JAMA Netw Open. 2021;4(9):e2125308.
30. Kühnle S, Martínez-Noël G, Leclere F, Hayes SD, Harper JW, Howley PM. Angelman syndrome-associated point mutations in the Zn(2+)-binding N-terminal (AZUL) domain of UBE3A ubiquitin ligase inhibit binding to the proteasome. J Biol Chem. 2018;293(47):18387–99.
31. Matentzoglu K, Scheffner M. Ubiquitin ligase E6-AP and its role in human disease. Biochem Soc Trans. 2008;36(Pt 5):797–801.
32. Thatte J, Banks L. Human Papillomavirus 16 (HPV-16), HPV-18, and HPV-31 E6 Override the Normal Phosphoregulation of E6AP Enzymatic Activity. J Virol. 2017;91(22): e01390-17.
33. Kępińska AP, Iyegbe CO, Vernon AC, Yolken R, Murray RM, Pollak TA. Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic: Mechanisms of Psychosis Risk. Front Psychiatry. 2020;11:72.
34. Di Marco B, Bonaccorso CM, Aloisi E, D'Antoni S, Catania MV. Neuro-Inflammatory Mechanisms in Developmental Disorders Associated with Intellectual Disability and Autism Spectrum Disorder: A Neuro- Immune Perspective. CNS Neurol Disord Drug Targets. 2016;15(4):448–63.
35. Bonfim TA, Giacon-Arruda BCC, Hermes-Uliana C, Galera SAF, Marcheti MA. Family experiences in discovering Autism Spectrum Disorder: implications for family nursing. Rev Bras Enferm. 2020;73(s6):e20190489.
36. Hirota T, King BH. Autism Spectrum Disorder: A Review. Jama. 2023;329(2):157–68.
37. Eigbe IJ, Gamboa CM, Gjini J, Mukherjee J, Dube S. Gut Microbiome and Nutrition Interplay in Regulating and Improving Autism Spectrum Disorder Related Social Symptoms. 2024.
38. Nisticò V, Iacono A, Goeta D, Tedesco R, Giordano B, Faggioli R, et al. Hypermobile spectrum disorders symptoms in patients with functional neurological disorders and autism spectrum disorders: A preliminary study. Front Psychiatry. 2022;13:943098.
39. Patel M, Atluri LM, Gonzalez NA, Sakhamuri N, Athiyaman S, Randhi B, et al. A Systematic Review of Mixed Studies Exploring the Effects of Probiotics on Gut-Microbiome to Modulate Therapy in Children With Autism Spectrum Disorder. Cureus. 2022;14(12):e32313.
40. Wang JCK, Baddock HT, Mafi A, Foe IT, Bratkowski M, Lin TY, et al. Structure of the p53 degradation complex from HPV16. Nat Commun. 2024;15(1):1842.
41. Billingsley CL, Chintala S, Katzenellenbogen RA. Post-Transcriptional Gene Regulation by HPV 16E6 and Its Host Protein Partners. Viruses. 2022;14(7).
42. Shimada M, Yamashita A, Saito M, Ichino M, Kinjo T, Mizuki N, et al. The human papillomavirus E6 protein targets apoptosis-inducing factor (AIF) for degradation. Sci Rep. 2020;10(1):14195.
43. Trajkovski V. Association between Autism Spectrum Disorder and Cancer-a Review from the Literature. Journal of Health and Rehabilitation Sciences. 2024;3(1):21–7.
44. Squarzanti DF, Sorrentino R, Landini MM, Chiesa A, Pinato S, Rocchio F, et al. Human papillomavirus type 16 E6 and E7 oncoproteins interact with the nuclear p53-binding protein 1 in an in vitro reconstructed 3D epithelium: new insights for the virus-induced DNA damage response. Virol J. 2018;15(1):176.
45. Bordonaro M. Hypothesis: Cancer Is a Disease of Evolved Trade-Offs Between Neoplastic Virulence and Transmission. J Cancer. 2018;9(10):1707–24.
46. Chaudhary P, Proulx J, Park IW. Ubiquitin-protein ligase E3A (UBE3A) mediation of viral infection and human diseases. Virus Res. 2023;335:199191.
47. Peng K, Liu R, Jia C, Wang Y, Jeong GH, Zhou L, et al. Regulation of O-Linked N-Acetyl Glucosamine Transferase (OGT) through E6 Stimulation of the Ubiquitin Ligase Activity of E6AP. Int J Mol Sci. 2021;22(19):10286.
48. Buel GR, Chen X, Chari R, O'Neill MJ, Ebelle DL, Jenkins C, et al. Structure of E3 ligase E6AP with a proteasome-binding site provided by substrate receptor hRpn10. Nat Commun. 2020;11(1):1291.
49. Romero-Masters JC, Lambert PF, Munger K. Molecular Mechanisms of MmuPV1 E6 and E7 and Implications for Human Disease. Viruses. 2022;14(10):2138.
50. Meyer U, Feldon J, Yee BK. A review of the fetal brain cytokine imbalance hypothesis of schizophrenia. Schizophr Bull. 2009;35(5):959–72.
51. de Bakker T, Journe F, Descamps G, Saussez S, Dragan T, Ghanem G, et al. Restoring p53 Function in Head and Neck Squamous Cell Carcinoma to Improve Treatments. Front Oncol. 2021;11:799993.
52. Nabati F, Moradi M, Mohabatkar H. In silico analyzing the molecular interactions of plant-derived inhibitors against E6AP, p53, and c-Myc binding sites of HPV type 16 E6 oncoprotein. Mol Biol Res Commun. 2020;9(2):71–82.
53. Al-Beltagi M, Saeed NK, Elbeltagi R, Bediwy AS, Aftab SAS, Alhawamdeh R. Viruses and autism: A Bi-mutual cause and effect. World J Virol. 2023;12(3):172–92.
54. Mohammadi Manesh M, Mohebbi A, Yasaghi M, Najafi Memar Z, Javid N, Taziki SA, et al. Low Prevalence of Borna Disease Virus RNA in Patients with Bipolar Major Depression and Schizophrenia in North of Iran. Iran J Virol. 2017;11(2):8-13.
55. Hidayatullah A, Putra WE, Sustiprijatno S, RIFA’I M, Widiastuti D, Heikal MF, et al. Concatenation of molecular docking and dynamics simulation of human papillomavirus type 16 E7 oncoprotein targeted ligands: In quest of cervical cancer’s treatment. Anais da Academia Brasileira de Ciências. 2023;95(suppl 1):e20220633.
56. Pintacuda G, Martín JM, Eggan KC. Mind the translational gap: using iPS cell models to bridge from genetic discoveries to perturbed pathways and therapeutic targets. Mol Autism. 2021;12(1):10.
57. Hong D, Iakoucheva LM. Therapeutic strategies for autism: targeting three levels of the central dogma of molecular biology. Transl Psychiatry. 2023;13(1):58.
58. Mehta R, Kuhad A, Bhandari R. Nitric oxide pathway as a plausible therapeutic target in autism spectrum disorders. Expert Opin Ther Targets. 2022;26(7):659–79.
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How to Cite
1.
Sheikhi N, Hajizadeh F, Sarvari J, Bazi Z, Moradi I, Moradi A. Autism and Human Papillomavirus (HPV) E6: A Comprehensive Review. Iran J Psychiatry. 2025;:1-11.
