HAMAP rule MF_04006

Accession	MF_04006
Dates	14-FEB-2017 (Created) 9-FEB-2023 (Last updated, Version 8)

Name

HPV_E6

Scope

Viruses; Papillomaviridae

Templates

P06930 (VE6_HPV05); P03126 (VE6_HPV16); P04019 (VE6_HPV11): [Recover all]

Triggered by

HAMAP; MF_04006 (Get profile general information and statistics)

Identifier

VE6

Protein name

RecName: Full=Protein E6;

Gene name

E6

Function	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 UBE3A/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/E6AP targets several other substrates to degradation via the proteasome including host DLG1 or NFX-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 BAK1, 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.
Subunit	Forms homodimers. Interacts with ubiquitin-protein ligase UBE3A/E6-AP and thus forms a complex with human TP53. Interacts with human NFX1 and MAGI3. Interacts with human IRF3; this interaction inhibits the establishment of antiviral state. Interacts with human TYK2; this interaction inhibits JAK-STAT activation by interferon alpha. Interacts with host DLG1; this interaction leads to the proteasomal degradation of DLG1.
Subcellular location	Host cytoplasm. Host nucleus.
Miscellaneous	Belongs to the high risk human alphapapillomavirus family. The cancer-causing human papillomavirus E6 protein has a unique carboxy terminal PDZ domain containing substrate.

Function	Plays a major role in the induction and maintenance of cellular transformation. E6 associates with host UBE3A/E6-AP ubiquitin-protein ligase and modulates its activity. Sequesters tumor suppressor TP53 in the host cytoplasm and modulates its activity by interacting with host EP300 that results in the reduction of TP53 acetylation and activation. In turn, apoptosis induced by DNA damage is inhibited. E6 protects also host keratinocytes from apoptosis by mediating the degradation of host BAK1. May also inhibit host immune response.
Subunit	Forms homodimers. Interacts with ubiquitin-protein ligase UBE3A/E6-AP; this interaction stimulates UBE3A ubiquitin activity. Interacts with host TP53 and EP300; this interaction inhibits TP53 activity.
Subcellular location	Host cytoplasm. Host nucleus.
Miscellaneous	Belongs to the low risk human alphapapillomavirus family. The cancer-causing human papillomavirus E6 protein has a unique carboxy terminal PDZ domain containing substrate but low risk E6s do not possess this domain.

Function	Plays a major role in the induction and maintenance of cellular transformation. E6 associates with host UBE3A/E6-AP ubiquitin-protein ligase and modulates its activity. Protects host keratinocytes from apoptosis by mediating the degradation of host BAK1. May also inhibit host immune response.
Subunit	Forms homodimers. Interacts with ubiquitin-protein ligase UBE3A/E6-AP; this interaction stimulates UBE3A ubiquitin activity. Interacts with host BAK1.
Subcellular location	Host cytoplasm. Host nucleus.
Similarity	Belongs to the papillomaviridae E6 protein family.

Activator
DNA-binding
Early protein
Host cytoplasm
Host nucleus
Host-virus interaction
Inhibition of host innate immune response by virus

Inhibition of host IRF3 by virus
Inhibition of host RLR pathway by virus

Metal-binding
Modulation of host cell apoptosis by virus
Transcription
Transcription regulation
Viral immunoevasion
Zinc
Zinc-finger

GO:0003677; Molecular function: DNA binding.
GO:0046872; Molecular function: metal ion binding.
GO:0006355; Biological process: regulation of DNA-templated transcription.
GO:0006351; Biological process: DNA-templated transcription.
GO:0039648; Biological process: modulation by symbiont of host protein ubiquitination.
GO:0039502; Biological process: suppression by virus of host type I interferon-mediated signaling pathway.

GO:0030165; Molecular function: PDZ domain binding.
GO:0039548; Biological process: suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity.

Pfam	PF00518; E6; 1;

From: VE6_HPV05 (P06930)

Key

From

To

Description

Tag

Condition

FTGroup

ZN_FING

41

77

C-x*-C

ZN_FING

114

150

C-x*-C

From: VE6_HPV16 (P03126)

MOTIF (Optional)

Cter-2

Cter

PDZ-binding domain

PDZ

T-x-[VL]

Size range	134-273 amino acids
Related rules	None
Fusion	None

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