Human Papillomavirus E5 Oncoprotein: Function and Potential Target for Antiviral Therapeutics

Müller, Marietta; Prescott, Emma L.; Wasson, Christopher W.; Macdonald, Andrew

doi:10.2217/fvl.14.99

Cited by 33 publications

(34 citation statements)

References 81 publications

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“…16E5 is known to be a trans-membrane protein with putative ER and GA localization 8 . By comparison, despite the hydrophobic nature of YIPF4, there is little experimental evidence for its predicted membrane association 19 .…”

Section: Resultsmentioning

confidence: 99%

“…HPV16 E5 (16E5) is a small hydrophobic protein consisting of 83 amino acids, which forms three putative trans-membrane α-helices and appears to multimerize into a hexameric viroporin 5 6 7 8 . It is the least understood of the three HPV oncoproteins and most information about it is derived from overexpression systems due to a lack of antibody detection reagents.…”

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confidence: 99%

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YIP1 family member 4 (YIPF4) is a novel cellular binding partner of the papillomavirus E5 proteins

Müller

Wasson

Bhatia

et al. 2015

Sci Rep

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E5 proteins are amongst the least understood of the Human Papillomavirus (HPV) encoded gene products. They are small, membrane-integrated proteins known to modulate a number of critical host pathways associated with pathogenesis including growth factor receptor signaling and immune evasion. Their role in the virus life cycle is less clear, indicating a role in the productive stages of the life cycle. However, a mechanism for this is currently lacking. Here we describe the identification of a novel binding partner of E5, YIPF4 using yeast two-hybrid analysis. YIPF4 is also a poorly characterized membrane spanning protein. Mutagenesis studies implicated the transmembrane regions of each protein as important for their interaction. Binding to YIPF4 was found for all E5 proteins tested suggesting that this interaction may mediate a conserved E5 function. In normal human keratinocytes YIPF4 expression was down-regulated upon differentiation and this reduction was partially rescued in cells harbouring HPV. Despite the conserved nature of the interaction with E5, siRNA mediated depletion of YIPF4 failed to impede two well-characterized functions of E5, namely EGFR trafficking or HLA class I presentation. Continued studies of YIPF4 are warranted to determine its role in the PV life cycle.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

YIP1 family member 4 (YIPF4) is a novel cellular binding partner of the papillomavirus E5 proteins

Müller

Wasson

Bhatia

et al. 2015

Sci Rep

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“…16E5 monomers oligomerize as homodimers or hexamers (Kell et al 1994;Gieswein et al 2003;Wetherill et al 2012). 16E5 has roles in cellular transformation, mitogenic signaling, immune evasion, intracellular protein trafficking, and apoptosis [reviewed in Müller et al (2015)].…”

Section: Human Papillomavirus E5mentioning

confidence: 99%

“…The C-terminal domain of 16E5 has been reported to bind the nuclear transport receptor karyopherin β3 (KNβ3) (Krawczyk et al 2008) and the Ca 2+ / phospholipid-/actin-binding protein calpactin I (Krawczyk et al 2011). Other reported interaction targets of 16E5 include the gap junction protein connexin 43 (Oelze et al 1995;Tomakidi et al 2000), growth factor receptor ErbB4 ), zinc transporter ZnT-1 (Lazarczyk et al 2008), transmembrane channel-like proteins EVER1 and EVER2 (Lazarczyk et al 2008), the putative ER ion channel A4 (Kotnik Halavaty et al 2014), and the Golgi-resident transmembrane protein YIPF4 (Müller et al 2015).…”

Section: Host Interactionsmentioning

confidence: 99%

Beyond Channel Activity: Protein-Protein Interactions Involving Viroporins

Torres

2018

Subcellular Biochemistry

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Viroporins are short polypeptides encoded by viruses. These small membrane proteins assemble into oligomers that can permeabilize cellular lipid bilayers, disrupting the physiology of the host to the advantage of the virus. Consequently, efforts during the last few decades have been focused towards the discovery of viroporin channel inhibitors, but in general these have not been successful to produce licensed drugs. Viroporins are also involved in viral pathogenesis by engaging in critical interactions with viral proteins, or disrupting normal host cellular pathways through coordinated interactions with host proteins. These protein-protein interactions (PPIs) may become alternative attractive drug targets for the development of antivirals. In this sense, while thus far most antiviral molecules have targeted viral proteins, focus is moving towards targeting host proteins that are essential for virus replication. In principle, this largely would overcome the problem of resistance, with the possibility of using repositioned existing drugs. The precise role of these PPIs, their strain- and host- specificities, and the structural determination of the complexes involved, are areas that will keep the fields of virology and structural biology occupied for years to come. In the present review, we provide an update of the efforts in the characterization of the main PPIs for most viroporins, as well as the role of viroporins in these PPIs interactions.

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“…Persistent infection with human papillomavirus (HPV) is the underlying cause of almost all cervical cancers, with the high-risk HPV16 and HPV18 types being the two most prevalent HPV types responsible (13). HPV-induced transformation is primarily driven by the E6 and E7 viral oncogenes (14,15), and this is achieved through the extensive manipulation of host cell signalling networks (16)(17)(18)(19)(20)(21). Critically, E6 and E7 promote the proteasomal degradation of the p53 and pRb tumour suppressors, by co-opting the E3 ligases E6associated protein (E6-AP) and a Cullin-2 ubiquitin ligase complex (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer

Morgan

Patterson

Barba-Moreno

et al. 2020

Preprint

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Ubiquitination is a critical regulator of cellular homeostasis. Aberrations in the addition or removal of ubiquitin can result in the development of cancer and key components of the ubiquitination machinery serve as oncogenes or tumour suppressors. An emerging target in the development of cancer therapeutics are the deubiquitinase (DUB) enzymes that remove ubiquitin from protein substrates. Whether this class of enzyme plays a role in cervical cancer has not been fully explored. By interrogating the cervical cancer data from the TCGA consortium, we noted that the DUB USP13 is amplified in approximately 15% of cervical cancer cases. We confirmed that USP13 expression was increased in cervical cancer cell lines, cytology samples from patients with cervical disease and in cervical cancer tissue. Depletion of USP13 inhibited cervical cancer cell proliferation. Mechanistically, USP13 bound to, deubiquitinated and stabilised Mcl-1, a pivotal member of the anti-apoptotic Bcl-2 family and the reduced Mcl-1 expression contributed to the observed proliferative defect. Importantly, the expression of USP13 and Mcl-1 proteins correlated in cervical cancer tissue. Finally, we demonstrated that depletion of USP13 expression or inhibition of USP13 enzymatic activity increased the sensitivity of cervical cancer cells to the BH3 mimetic inhibitor ABT-263. Together, our data demonstrates that USP13 is a potential oncogene in cervical cancer that functions to stabilise the pro-survival protein Mcl-1, offering a potential therapeutic target for these cancers.

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Human Papillomavirus E5 Oncoprotein: Function and Potential Target for Antiviral Therapeutics

Cited by 33 publications

References 81 publications

YIP1 family member 4 (YIPF4) is a novel cellular binding partner of the papillomavirus E5 proteins

YIP1 family member 4 (YIPF4) is a novel cellular binding partner of the papillomavirus E5 proteins

Beyond Channel Activity: Protein-Protein Interactions Involving Viroporins

The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer

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