Upsetting the Balance: When Viruses Manipulate Cell Polarity Control

Thomas, Miranda; Banks, Lawrence

doi:10.1016/j.jmb.2018.04.016

Cited by 26 publications

(28 citation statements)

References 258 publications

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“…A small subset of Human Papillomavirus (HPV) types, known as high-risk HPV types (mainly HPV-16 and HPV-18), are the causative agents of cervical cancer and a large number of other human malignancies [1,2]. Persistent expression of HPV E6 and E7 oncoproteins leads to the development of cancer and is known to be the major hallmark of high-risk HPV-induced carcinogenesis [3][4][5][6]. The E7 oncoprotein was identified as the main driver of tumour initiation through targeting and abrogating the function of retinoblastoma (Rb) protein, thus overriding cell cycle regulation [7].…”

Section: Introductionmentioning

confidence: 99%

Identification of E6AP-independent degradation targets of HPV E6

Vats

Thatte

Banks

2019

Journal of General Virology

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The high-risk Human Papillomavirus (HPV) E6 oncoprotein is known to contribute to human malignancy by targeting several of its cellular substrates through the ubiquitin-mediated degradation pathway. Previous studies have revealed that E6 interacts with the E6AP ubiquitin-protein ligase and directs its ubiquitylation activity toward several specific cellular proteins, one of the most important of which is p53. However, the role of E6AP in the degradation of many other E6 substrates is still ambiguous because loss of E6AP also induces a loss of E6 expression. To examine this further, we used CRISPR-edited E6AP knockout cells to perform E6 degradation assays in the presence of a catalytically inactive mutant form of E6AP, thus ensuring the stabilization of E6 but with the ligase itself being functionally inactive. Using this system, we found that E6 can mediate the degradation of several PDZ domain-containing proteins independently of E6AP ubiquitin ligase activity. This study thus opens up ways to investigate other possible components of the cellular ubiquitin proteasome pathway that E6 might utilize to target these substrates.

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Section: Introductionmentioning

confidence: 99%

Identification of E6AP-independent degradation targets of HPV E6

Vats

Thatte

Banks

2019

Journal of General Virology

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“…through E6AP-mediated ubiquitination, while E7 interacts with the PDZ domain of cellular proteins, such as retinoblastoma protein pRb, to induce cellular transformation. In addition to p53 and pRb, high-risk HPV E6 and E7 were identified to associate with multiple cellular proteins and contribute to neoplastic progression (1)(2)(3)(4)(5)(6). Due to the critical roles of HPV E6 and E7 in tumorigenesis, these viral proteins were potential targets for the therapy of HPV-related cancers (7).…”

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confidence: 99%

Human Papillomavirus E6/E7 and Long Noncoding RNA TMPOP2 Mutually Upregulated Gene Expression in Cervical Cancer Cells

Liu

et al. 2019

J Virol

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TMPOP2 was previously suggested to be an oncogenic long noncoding RNA which is excessively expressed in cervical cancer cells and inhibits E-cadherin gene expression by recruiting transcription repressor EZH2 to the gene promoter. So far, the function and regulation of TMPOP2 in cervical cancer remain largely unknown. Herein, we found that TMPOP2 expression was correlated with human papillomavirus 16/18 (HPV16/18) E6 and E7 in cervical cancer cell lines CaSki and HeLa. Tumor suppressor p53, which is targeted for degradation by HPV16/18, was demonstrated to associate with two p53 response elements in the TMPOP2 promoter to repress the transcription of the TMPOP2 gene. Reciprocally, ectopic expression of TMPOP2 was demonstrated to sequester tumor repressor microRNAs (miRNAs) miR-375 and miR-139 which target HPV16/18 E6/E7 mRNA and resulted in an upregulation of HPV16/18 E6/E7 genes. Thereby, HPV16/18 E6/E7 and the long noncoding RNA (lncRNA) TMPOP2 form a positive feedback loop to mutually derepress gene expression in cervical cancer cells. Moreover, results of RNA sequencing and cell cycle analysis showed that knockdown of TMPOP2 impaired the expression of cell cycle genes, induced cell cycle arrest, and inhibited HeLa cell proliferation. Together, our results indicate that TMPOP2 and HPV16/18 E6/E7 mutually strengthen their expression in cervical cancer cells to enhance tumorigenic activities. IMPORTANCE Human papillomaviruses 16 and 18 (HPV16/18) are the main causative agents of cervical cancer. Viral proteins HPV16/18 E6 and E7 are constitutively expressed in cancer cells to maintain oncogenic phenotypes. Accumulating evidences suggest that HPVs are correlated with the deregulation of long noncoding RNAs (lncRNAs) in cervical cancer, although the mechanism was unexplored in most cases. TMPOP2 is a newly identified lncRNA excessively expressed in cervical cancer. However, the mechanism for the upregulation of TMPOP2 in cervical cancer cells remains largely unknown and its relationship with HPVs is still elusive. The significance of our research is in revealing the mutual upregulation of HPV16/18 E6/E7 and TMPOP2 with the molecular mechanisms explored. This study will expand our understandings of the oncogenic activities of human papillomaviruses and lncRNAs. KEYWORDS HPV E6/E7, cervical cancer, lncRNA TMPOP2, miRNAs, p53 H igh-risk human papillomaviruses (HPVs), primarily including HPV16 and HPV18, are causative agents of cervical cancer, which is one of the leading lethal female cancers worldwide. Integration of HPV DNA into the host cell genome results in the constitutive high expression of two viral oncogenes, HPV E6 and E7, under the control of cellular transcription factors. Viral protein E6 promotes p53 protein degradation FIG 4 TMPOP2 reciprocally regulated the expression of HPV E6/E7 in cervical cancer cells. (A) The efficacy of TMPOP2 knockdown in HeLa cells. (B)The protein levels of HPV18 E6/E7 were decreased following TMPOP2 knockdown. GAPDH was the protein loading control. (C) The mRNA levels of HPV1...

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“…Cell polarity proteins can regulate molecular segregation processes within the subcellular space to make a cell more fit to perform certain biologic functions, such as proliferation, apoptosis, stress adaptation, stemness, and organelle biology (40). Cell polarity proteins are frequently targeted by different viruses, which affect not only host cell polarity but also many other cellular processes (39). Given the evolutionary arms race between hosts and pathogens, the cell polarity induced in activated cells of the immune system would be a natural target for virus interactions.…”

Section: Discussionmentioning

confidence: 99%

“…A complex genotype-phenotype association is required to systematically search for PDZbms in the following: 1) host endogenous interactions for specific cellular functions, 2) viral interactions with host PDZ proteins (which may be either predicted or already described), and 3) other pathogens (primarily bacteria). PDZbm-PDZ domain binding is subject to a high level of specificity and control, conditioned by the steric and electrostatic characteristics of the respective sequences (39), which could be used to predict the PDZ proteins and their interactions in immune cells. Remarkably, the high specificity of PDZbm-PDZ domain interactions is accompanied by low affinities (1) (at least 3 orders of magnitude weaker than Ag-antibody binding reactions), which makes them an easy target in dynamic, coevolutionary processes such as viral hijacking.…”

Section: Discussionmentioning

confidence: 99%

“…Because a virus tends to take over the cellular machinery of the host cell, of which polarity proteins are vital elements, one can speculate that the targeting of polarity proteins by the virus may bias cellular fitness as a crucial step toward making the subcellular environment more apt for its own replication, modifying signaling pathways and cellular and tissue homeostasis (39,40). The recent description of targeting of polarity proteins by viruses in additional immune cells, including APCs, (26) led us to hypothesize that modification of the cellular fitness landscape may occur as a common and widespread mechanism for immune evasion by viruses and possibly other pathogens.…”

Section: Viral Targeting Of Pdz Proteins In the Immune Systemmentioning

confidence: 99%

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Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism

Gutiérrez‐González¹,

Santos‐Mendoza

2019

FASEB j.

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PDZ proteins are highly conserved through evolution; the principal function of this large family of proteins is to assemble protein complexes that are involved in many cellular processes, such as cell‐cell junctions, cell polarity, recycling, or trafficking. Many PDZ proteins that have been identified as targets of viral pathogens by promoting viral replication and spread are also involved in epithelial cell polarity. Here, we briefly review the PDZ polarity proteins in cells of the immune system to subsequently focus on our hypothesis that the viral PDZ‐dependent targeting of PDZ polarity proteins in these cells may alter the cellular fitness of the host to favor that of the virus; we further hypothesize that this modification of the cellular fitness landscape occurs as a common and widespread mechanism for immune evasion by viruses and possibly other pathogens.—Gutiérrez‐González, L. H., Santos‐Mendoza, T. Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism. FASEB J. 33, 10607–10617 (2019). http://www.fasebj.org

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Upsetting the Balance: When Viruses Manipulate Cell Polarity Control

Cited by 26 publications

References 258 publications

Identification of E6AP-independent degradation targets of HPV E6

Identification of E6AP-independent degradation targets of HPV E6

Human Papillomavirus E6/E7 and Long Noncoding RNA TMPOP2 Mutually Upregulated Gene Expression in Cervical Cancer Cells

Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism

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