Inhibition of E6-induced Degradation of its Cellular Substrates by Novel Blocking Peptides

Grm, Helena Sterlinko; Weber, Malte; Elston, R. N.; McIntosh, Pauline B.; Griffin, Heather; Banks, Lawrence; Doorbar, John

doi:10.1016/j.jmb.2003.10.079

Cited by 44 publications

(40 citation statements)

References 43 publications

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“…The E6-dependent degradation of Dlg (46) and MAGI-1, -2, and -3 was suggested to occur independently of the ubiquitin ligase E6AP (14,60). We found that shRNA-mediated silencing of E6AP did not interfere with 18 E6-dependent degradation of PATJ.…”

Section: Discussionmentioning

confidence: 64%

PATJ, a Tight Junction-Associated PDZ Protein, Is a Novel Degradation Target of High-Risk Human Papillomavirus E6 and the Alternatively Spliced Isoform 18 E6*

Storrs

Silverstein

2007

J Virol

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The E6 protein from high-risk human papillomavirus types interacts with and degrades several PDZ domain-containing proteins that localize to adherens junctions or tight junctions in polarized epithelial cells. We have identified the tight junction-associated multi-PDZ protein PATJ (PALS1-associated TJ protein) as a novel binding partner and degradation target of high-risk types 16 and 18 E6. PATJ functions in the assembly of the evolutionarily conserved CRB-PALS1-PATJ and Par6-aPKC-Par3 complexes and is critical for the formation of tight junctions in polarized cells. The ability of type 18 E6 full-length to bind to, and the subsequent degradation of, PATJ is dependent on its C-terminal PDZ binding motif. We demonstrate that the spliced 18 E6* protein, which lacks a C-terminal PDZ binding motif, associates with and degrades PATJ independently of full-length 18 E6. Thus, PATJ is the first binding partner that is degraded in response to both isoforms of 18 E6. The ability of E6 to utilize a non-E6AP ubiquitin ligase for the degradation of several PDZ binding partners has been suggested. We also demonstrate that 18 E6-mediated degradation of PATJ is not inhibited in cells where E6AP is silenced by shRNA. This suggests that the E6-E6AP complex is not required for the degradation of this protein target.Human papillomaviruses (HPVs) are DNA tumor viruses that infect basal cells of the mucosal or cutaneous epithelium, where they cause proliferative lesions on genital tissues, the upper respiratory tract, and skin. Papillomas induced by highrisk mucosal HPV types, of which 16, 18, 31, and 45 are predominant, are inherently oncogenic and associated with the vast majority of cervical cancers (64) and many oral cancers (9). In contrast, low-risk types, such as 6 and 11, are rarely associated with carcinogenesis (10). HPV-associated carcinogenesis is attributed to the high-risk specific activities of the viral gene products E6 and E7, and introduction of these genes from HPV types 16 or 18 can induce immortalization of primary human keratinocytes (16,35). Studies using transgenic mice that express 16 E6 and/or 16 E7 have revealed that E7 initiates tumor formation, while E6 induces tumor promotion and progression, in the skin and cervix of transgenic animals (13, 47, 58).High-risk E6 proteins are multifunctional and associate with functionally diverse cellular proteins. Degradation of p53 by the E6-E6AP complex (17) is a property of high-risk E6 types, although this activity alone is not sufficient for E6-dependent immortalization activity in tissue culture or tumorigenesis in transgenic animals. For example, certain E6 mutant proteins that fail to degrade p53 retain their ability to immortalize primary cells (30,45). Moreover, the phenotypes of E6 transgenic mice are not observed in p53-null mice (59).A 4-amino-acid PDZ binding motif (X-S/T-X-V/L, where X is any amino acid) is present at the carboxy termini of all known high-risk mucosal HPV E6 proteins. The conservation of this motif among high-risk, but not low-risk, muco...

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Section: Discussionmentioning

confidence: 64%

PATJ, a Tight Junction-Associated PDZ Protein, Is a Novel Degradation Target of High-Risk Human Papillomavirus E6 and the Alternatively Spliced Isoform 18 E6*

Storrs

Silverstein

2007

J Virol

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“…All of these approaches have been shown to inhibit the expression of HPV E6 mRNA and protein, leading to cell growth suppression and a reduction of tumorigenicity in vivo. In addition, blocking E6 activity by using a therapeutic peptide was shown to induce apoptosis of HPV-positive cancer cells and to inhibit E6-induced degradation of its cellular substrates, such as p53, Dlg, and the membrane-associated guanylate kinase inverted family of proteins (48,49).…”

Section: Discussionmentioning

confidence: 99%

Pitx2a Binds to Human Papillomavirus Type 18 E6 Protein and Inhibits E6-mediated P53 Degradation in HeLa Cells

Wei

2005

Journal of Biological Chemistry

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Binding of high risk human papillomavirus (HPV) E6 protein to E6-associated protein (E6AP), a cellular ubiquitin-protein ligase, enables E6AP to ubiquitinate p53, leading to p53 degradation in cervical cancer cells such as HeLa cells. Here we report that Pitx2a, a bicoid-type homeodomain transcription factor, can bind to HPV E6 protein and inhibit E6/E6AP-mediated p53 degradation. Deletion of the Pitx2a homeodomain abrogates its ability to bind to HPV E6 protein and to induce p53 accumulation in HeLa cells, suggesting that the homeodomain of Pitx2a is essential for inhibition of E6/E6AP-mediated p53 degradation. Recombinant Pitx2a can also block E6/E6AP-mediated p53 degradation in vitro, indicating that this function of Pitx2a is independent of its transcription activity. Pitx2a does not regulate Hdm2-mediated p53 degradation, because Pitx2a does not affect p53 protein levels in HPV-negative cells, such as HCT116, U2OS, and C33A cells. In addition, Pitx2a-induced p53 is transcriptionally active and maintains its specific DNA binding activity in HeLa cells. Taken together, these findings suggest that, by binding to E6, Pitx2a interferes with E6/E6AP-mediated p53 degradation, leading to the accumulation of functional p53 protein in HeLa cells.

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“…HR-HPV E6 PDZ binding can mediate suprabasal cell proliferation and this is thought to occur by uncoupling the cell proliferation and polarity control that exist in a differentiated epithelium (Sterlinko et al, 2004). LR-HPV E6 does not contain the PDZ-binding motif and therefore cannot target these proteins.…”

Section: E6 Proteinmentioning

confidence: 99%

Human Papillomavirus: Biology and Pathogenesis

Fernandes¹,

Fernandes²

2012

Human Papillomavirus and Related Diseases - From Bench to Bedside - A Clinical Perspective

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Inhibition of E6-induced Degradation of its Cellular Substrates by Novel Blocking Peptides

Cited by 44 publications

References 43 publications

PATJ, a Tight Junction-Associated PDZ Protein, Is a Novel Degradation Target of High-Risk Human Papillomavirus E6 and the Alternatively Spliced Isoform 18 E6*

PATJ, a Tight Junction-Associated PDZ Protein, Is a Novel Degradation Target of High-Risk Human Papillomavirus E6 and the Alternatively Spliced Isoform 18 E6*

Pitx2a Binds to Human Papillomavirus Type 18 E6 Protein and Inhibits E6-mediated P53 Degradation in HeLa Cells

Human Papillomavirus: Biology and Pathogenesis

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