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Structural highlights

Function

VE6_HPV16 Plays a major role in the induction and maintenance of cellular transformation. Acts mainly as an oncoprotein by stimulating the destruction of many host cell key regulatory proteins. E6 associates with host E6-AP ubiquitin-protein ligase, and inactivates tumor suppressors TP53 and TP73 by targeting them to the 26S proteasome for degradation. In turn, DNA damage and chromosomal instabilities increase and lead to cell proliferation and cancer development. The complex E6/E6P targets several other substrates to degradation via the proteasome including host NFX1-91, a repressor of human telomerase reverse transcriptase (hTERT). The resulting increased expression of hTERT prevents the shortening of telomere length leading to cell immortalization. Other cellular targets including Bak, Fas-associated death domain-containing protein (FADD) and procaspase 8, are degraded by E6/E6AP causing inhibition of apoptosis. E6 also inhibits immune response by interacting with host IRF3 and TYK2. These interactions prevent IRF3 transcriptional activities and inhibit TYK2-mediated JAK-STAT activation by interferon alpha resulting in inhibition of the interferon signaling pathway.^{[1] [2] [3]}

References

1. ↑ Klingelhutz AJ, Foster SA, McDougall JK. Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature. 1996 Mar 7;380(6569):79-82. PMID:8598912 doi:http://dx.doi.org/10.1038/380079a0
2. ↑ Ronco LV, Karpova AY, Vidal M, Howley PM. Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev. 1998 Jul 1;12(13):2061-72. PMID:9649509
3. ↑ Li S, Labrecque S, Gauzzi MC, Cuddihy AR, Wong AH, Pellegrini S, Matlashewski GJ, Koromilas AE. The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-alpha. Oncogene. 1999 Oct 14;18(42):5727-37. PMID:10523853 doi:http://dx.doi.org/10.1038/sj.onc.1202960
4. ↑ Zanier K, Ould M'hamed Ould Sidi A, Boulade-Ladame C, Rybin V, Chappelle A, Atkinson A, Kieffer B, Trave G. Solution Structure Analysis of the HPV16 E6 Oncoprotein Reveals a Self-Association Mechanism Required for E6-Mediated Degradation of p53. Structure. 2012 Apr 4;20(4):604-17. Epub 2012 Apr 3. PMID:22483108 doi:10.1016/j.str.2012.02.001