Viruses exploit the function of epidermal growth factor receptor

Zheng, Kai; Kitazato, Kaio; Wang, Yifei

doi:10.1002/rmv.1796

Cited by 76 publications

(92 citation statements)

References 104 publications

(130 reference statements)

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“…Upon stimulation with epidermal growth factor (EGF), the EGF-EGFR complex undergoes internalization through clathrin-meditated endocytosis and is targeted by lysosomes for degradation or recycling. 35 As shown in Figure 4C, Ro and CQ inhibited EGF-triggered EGFR degradation.…”

Section: Ro Treatment Inhibits Lysosomal Activitymentioning

confidence: 92%

Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint

Zheng

Wang

et al. 2016

Autophagy

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Modulation of autophagy has been increasingly regarded as a promising cancer therapeutic approach. In this study, we screened several ginsenosides extracted from Panax ginseng and identified ginsenoside Ro (Ro) as a novel autophagy inhibitor. Ro blocked the autophagosome-lysosome fusion process by raising lysosomal pH and attenuating lysosomal cathepsin activity, resulting in the accumulation of the autophagosome marker MAP1LC3B/LC3B and SQSTM1/p62 (sequestosome 1) in various esophageal cancer cell lines. More detailed studies demonstrated that Ro activated ESR2 (estrogen receptor 2), which led to the activation of NCF1/p47(PHOX) (neutrophil cytosolic factor 1), a subunit of NADPH oxidase, and subsequent reactive oxygen species (ROS) production. Treatment with siRNAs or inhibitors of the ESR2-NCF1-ROS axis, such as N-acetyl-L-cysteine (NAC), diphenyleneiodonium chloride (DPI), apocynin (ACN), Tiron, and Fulvestrant apparently decreased Ro-induced LC3B-II, GFP-LC3B puncta, and SQSTM1, indicating that ROS instigates autophagic flux inhibition triggered by Ro. More importantly, suppression of autophagy by Ro sensitized 5-fluorouracil (5-Fu)-induced cell death in chemoresistant esophageal cancer cells. 5-Fu induced prosurvival autophagy, and by inhibiting such autophagy, siRNAs against BECN1/beclin 1, ATG5, ATG7, and LC3B enhanced 5-Fu-induced autophagy-associated and apoptosis-independent cell death. We observed that Ro potentiates 5-Fu cytotoxicity via delaying CHEK1 (checkpoint kinase 1) degradation and downregulating DNA replication process, resulting in the delayed DNA repair and the accumulation of DNA damage. In summary, these data suggest that Ro is a novel autophagy inhibitor and could function as a potent anticancer agent in combination therapy to overcome chemoresistance.

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Section: Ro Treatment Inhibits Lysosomal Activitymentioning

confidence: 92%

Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint

Zheng

Wang

et al. 2016

Autophagy

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“…In Ad-infected cells, the immediate early Ad E1A transcriptional activator downregulates EGFR, an effect hypothesized to isolate virus-infected cells from host-specific signals such as the EGFR-dependent induction of the neutrophil chemoattractant interleukin-8 (IL-8) (29,52). In contrast, our results showed that Ad E4-ORF1, the expression of which depends on E1A in Ad-infected cells, binds and activates EGFR (Fig.…”

Section: Discussionmentioning

confidence: 72%

“…Numerous pathogenic human viruses usurp EGFR or the Ras/ Mek/Erk pathway to facilitate virus entry, replication, assembly, host immune surveillance evasion, inflammation, pathogenesis, and transmission (29,51). In Ad-infected cells, the immediate early Ad E1A transcriptional activator downregulates EGFR, an effect hypothesized to isolate virus-infected cells from host-specific signals such as the EGFR-dependent induction of the neutrophil chemoattractant interleukin-8 (IL-8) (29,52).…”

Section: Discussionmentioning

confidence: 99%

“…Transphosphorylation of EGFR and InsR/IGF1R and their synergistic coactivation of common effectors, activities known as receptor cross talk, have also been reported (28). Furthermore, proteins encoded by the Ad early region 1A gene (E1A) and the Ad early region 3 gene (E3) downregulate EGFR and/or InsR/IGF1R (29,30), and the Ad type 36 E4-ORF1 protein blocks InsR-mediated tyrosine phosphorylation of insulin receptor substrate 1 (31), although the functions of these effects during the Ad life cycle are not known. Also notable are studies showing that treatment of E4-ORF1-expressing rodent fibroblasts with a PI3K inhibitor drug exposes the capacity of E4-ORF1 to activate the Ras/Mek/Erk pathway and that an undetermined Ad5 gene activates this pathway at the late phase of infection in human epithelial cells (19,32).…”

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confidence: 98%

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Adenovirus E4-ORF1 Dysregulates Epidermal Growth Factor and Insulin/Insulin-Like Growth Factor Receptors To Mediate Constitutive Myc Expression

Kong

Kumar

Taruishi

et al. 2015

J Virol

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The E4-ORF1 protein encoded by human adenovirus stimulates viral replication in human epithelial cells by binding and activating cellular phosphatidylinositol 3-kinase (PI3K) at the plasma membrane and cellular Myc in the nucleus. In this study, we showed that E4-ORF1 hijacks the tyrosine kinase activities of cellular epidermal growth factor receptor (EGFR) and insulin receptor (InsR)/insulin-like growth factor receptor 1 (IGF1R), as well as the lipid kinase activity of PI3K, to mediate constitutive Myc protein expression. We additionally demonstrated that EGFR contributes to constitutive Myc expression through the capacity of E4-ORF1 to induce ligand-independent EGFR activation and stimulation of the Ras/Mek/Erk pathway, the latter activity of which was conserved by human adenoviruses. Results further suggested that EGFR normally forms a complex with the cellular PDZ protein Discs Large 1 (Dlg1), a component of the Dlg1:E4-ORF1:PI3K ternary complex that mediates E4-ORF1-induced PI3K activation, and that E4-ORF1 binds the Dlg1:EGFR complex and promotes the association of EGFR with InsR and IGF1R. In addition to its role in constitutive Myc expression, InsR/IGF1R also negatively regulates EGFR autophosphorylation and EGFR-mediated Ras/Mek/Erk signaling, and data suggested that E4-ORF1 binding to Dlg1 antagonizes these activities. Collectively, our findings suggest that in human epithelial cells, E4-ORF1 targets EGFR, InsR/IGF1R, and PI3K at the plasma membrane to activate cytosolic signaling pathways that sustain Myc protein levels in the nucleus. We postulate that E4-ORF1-induced constitutive Myc expression functions to ensure the formation of nuclear E4-ORF1:Myc complexes, which have been shown to activate Myc and to enhance adenovirus replication. O ver 60 human adenovirus (Ad) serotypes are classified into seven subgroups (subgroups A through G) based on oncogenic, hemagglutination, and virion structural protein properties as well as genome sequence similarity (1). Ad is a human pathogen primarily associated with mild, self-limited respiratory diseases but additionally causes gastroenteritis, conjunctivitis, cystitis, and skin rashes (1). Certain viral serotypes, such as Ad type 14 (Ad14), can cause life-threatening symptoms that require hospitalization for up to 40% of otherwise healthy individuals (2), and Ad infections of neonates and immunosuppressed patients are associated with high morbidity and mortality rates (3). However, current treatments for severe Ad infections are controversial and carry significant risks for adverse events (1). Ad is also exploited as a vector for vaccination and gene and cancer therapy as well as a tool of discovery to reveal fundamental mechanisms of the cell and mechanisms for cancer development (1).The Ad early region 4 open reading frame 1 gene (E4-ORF1) encodes a 14-kDa protein required for optimal viral replication (4-6). In humans, subgroup D Ad9 is associated with eye infections (1), whereas Ad9 inoculation into experimental animals elicits estrogen-dependent m...

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“…Another conceivable mechanism by which HDAC6 regulates HIVinduced cell fusion and infection is that HDAC6 may regulate actin reorganization to inhibit viral entry through receptor-mediated endocytosis or pH-dependent fusion between HIV-1 and plasma membrane. Cortical actin located immediately beneath the plasma membrane is the first obstacle encountered by the viruses upon infection, and reorganization of the cellular actin cytoskeleton significantly affects virus entry [72]. There is increasing evidence showing the connection between actin regulation and HDAC6 [73,74], and cortactin, an important regulator of actin assembly and disassembly, can also be tightly controlled by HDAC6 [24].…”

Section: Fusion and Entrymentioning

confidence: 99%

Cellular defence or viral assist: the dilemma of HDAC6

Zheng

Jiang

et al. 2017

Journal of General Virology

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Histone deacetylase 6 (HDAC6) is a unique cytoplasmic deacetylase that regulates various important biological processes by preventing protein aggregation and deacetylating different non-histone substrates including tubulin, heat shock protein 90, cortactin, retinoic acid inducible gene I and b-catenin. Growing evidence has indicated a dual role for HDAC6 in viral infection and pathogenesis: HDAC6 may represent a host defence mechanism against viral infection by modulating microtubule acetylation, triggering antiviral immune response and stimulating protective autophagy, or it may be hijacked by the virus to enhance proinflammatory response. In this review, we will highlight current data illustrating the complexity and importance of HDAC6 in viral pathogenesis. We will summarize the structure and functional specificity of HDAC6, and its deacetylaseand ubiquitin-dependent activity in key cellular events in response to virus infection. We will also discuss how HDAC6 exerts its direct or indirect histone modification ability in viral lytic-latency switch.

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Viruses exploit the function of epidermal growth factor receptor

Cited by 76 publications

References 104 publications

Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint

Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint

Adenovirus E4-ORF1 Dysregulates Epidermal Growth Factor and Insulin/Insulin-Like Growth Factor Receptors To Mediate Constitutive Myc Expression

Cellular defence or viral assist: the dilemma of HDAC6

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