Human Cytokinome Analysis for Interferon Response

Al-Yahya, Suhad; Mahmoud, Linah; Al-Zoghaibi, Fahad; Altuhami, Abdullah; Amer, Haithem; Almajhdi, Fahad N.; Polyak, Stephen J.; Khabar, Khalid S.A.

doi:10.1128/jvi.03729-14

Cited by 16 publications

(12 citation statements)

References 44 publications

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“…Since STAT1 homodimers bind to gamma activation site (GAS) promoter sequences in response to type II IFN (IFN-γ) stimulation, the preservation of STAT1 may prime the cells to respond to type II interferon as the type I response abates. This mechanism is consistent with previous reports of both the induction of a GAS binding factor and GAS promoter driven transcription by IFN-α and IFN-β [91, 92]. Indeed in separate experiments, we observed that induction of a GAS reporter gene by interferon-γ is more pronounced in PDLIM2 K/O cells than in the parental Huh7.5 cells.…”

Section: Discussionsupporting

confidence: 93%

HCV and flaviviruses hijack cellular mechanisms for nuclear STAT2 degradation: Up-regulation of PDLIM2 suppresses the innate immune response

et al. 2019

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Host encounters with viruses lead to an innate immune response that must be rapid and broadly targeted but also tightly regulated to avoid the detrimental effects of unregulated interferon expression. Viral stimulation of host negative regulatory mechanisms is an alternate method of suppressing the host innate immune response. We examined three key mediators of the innate immune response: NF-KB, STAT1 and STAT2 during HCV infection in order to investigate the paradoxical induction of an innate immune response by HCV despite a multitude of mechanisms combating the host response. During infection, we find that all three are repressed only in HCV infected cells but not in uninfected bystander cells, both in vivo in chimeric mouse livers and in cultured Huh7.5 cells after IFNα treatment. We show here that HCV and Flaviviruses suppress the innate immune response by upregulation of PDLIM2, independent of the host interferon response. We show PDLIM2 is an E3 ubiquitin ligase that also acts to stimulate nuclear degradation of STAT2. Interferon dependent relocalization of STAT1/2 to the nucleus leads to PDLIM2 ubiquitination of STAT2 but not STAT1 and the proteasome-dependent degradation of STAT2, predominantly within the nucleus. CRISPR/Cas9 knockout of PDLIM2 results in increased levels of STAT2 following IFNα treatment, retention of STAT2 within the nucleus of HCV infected cells after IFNα stimulation, increased interferon response, and increased resistance to infection by several flaviviruses, indicating that PDLIM2 is a global regulator of the interferon response.

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Section: Discussionsupporting

confidence: 93%

HCV and flaviviruses hijack cellular mechanisms for nuclear STAT2 degradation: Up-regulation of PDLIM2 suppresses the innate immune response

et al. 2019

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“…IRF-1 plays a critical role in innate antiviral response and the functional response of STAT1α, IFN-γ, and TNF-α to IFN-signaling signifies the cell's proper antiviral potential. 56 , 57 Hence, these ex vivo observations suggest that modest reduction in endogenous IRF-1 level, such as that observed in these HESN women, does not affect host cellular IFN responsiveness, the key antiviral innate function.…”

Section: Resultsmentioning

confidence: 70%

Reducing IRF-1 to Levels Observed in HESN Subjects Limits HIV Replication, But Not the Extent of Host Immune Activation

Plesniarski

et al. 2015

Molecular Therapy - Nucleic Acids

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Cells from women who are epidemiologically deemed resistant to HIV infection exhibit a 40–60% reduction in endogenous IRF-1 (interferon regulatory factor-1), an essential regulator of host antiviral immunity and the early HIV replication. This study examined the functional consequences of reducing endogenous IRF-1 on HIV-1 replication and immune response to HIV in natural HIV target cells. IRF-1 knockdown was achieved in ex vivo CD4+ T cells and monocytes with siRNA. IRF-1 level was assessed using flow cytometry, prior to infection with HIV-Bal, HIV-IIIB, or HIV-VSV-G. Transactivation of HIV long terminal repeats was assessed by p24 secretion (ELISA) and Gag expression (reverse transcription–polymerase chain reaction (RT–PCR)). The expression of IRF-1–regulated antiviral genes was quantitated with RT–PCR. A modest 20–40% reduction in endogenous IRF-1 was achieved in >87% of ex vivo–derived peripheral CD4+ T cells and monocytes, resulted in >90% reduction in the transactivation of the HIV-1 genes (Gag, p24) and, hence, HIV replication. Curiously, these HIV-resistant women demonstrated normal immune responses, nor an increased susceptibility to other infection. Similarly, modest IRF-1 knockdown had limited impact on the magnitude of HIV-1–elicited activation of IRF-1–regulated host immunologic genes but resulted in lessened duration of these responses. These data suggest that early expression of HIV-1 genes requires a higher IRF-1 level, compared to the host antiviral genes. Together, these provide one key mechanism underlying the natural resistance against HIV infection and further suggest that modest IRF-1 reduction could effectively limit productive HIV infection yet remain sufficient to activate a robust but transient immune response.

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“…BTC transgenic mice also develop urothelial hyperplasia and show sex-dependent reduction in urinary protein content, which appears to be independent of EGFR signaling, suggesting a role for ERBB4 48 . BTC has also been identified as a novel modulator of interferon (IFN) response and enhances the anti-viral action of IFN 49 . In a large cytokine and chemokine screen to modulate IFN responses, BTC was identified as one of the most potent modulators of the IFN response.…”

Section: Aspects Of Individual Ligandsmentioning

confidence: 99%

EGF receptor ligands: recent advances

2016

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Seven ligands bind to and activate the mammalian epidermal growth factor (EGF) receptor (EGFR/ERBB1/HER1): EGF, transforming growth factor-alpha (TGFA), heparin-binding EGF-like growth factor (HBEGF), betacellulin (BTC), amphiregulin (AREG), epiregulin (EREG), and epigen (EPGN). Of these, EGF, TGFA, HBEGF, and BTC are thought to be high-affinity ligands, whereas AREG, EREG, and EPGN constitute low-affinity ligands. This focused review is meant to highlight recent studies related to actions of the individual EGFR ligands, the interesting biology that has been uncovered, and relevant advances related to ligand interactions with the EGFR.

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Human Cytokinome Analysis for Interferon Response

Cited by 16 publications

References 44 publications

HCV and flaviviruses hijack cellular mechanisms for nuclear STAT2 degradation: Up-regulation of PDLIM2 suppresses the innate immune response

HCV and flaviviruses hijack cellular mechanisms for nuclear STAT2 degradation: Up-regulation of PDLIM2 suppresses the innate immune response

Reducing IRF-1 to Levels Observed in HESN Subjects Limits HIV Replication, But Not the Extent of Host Immune Activation

EGF receptor ligands: recent advances

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