Activation of a novel ULK1-MLK3-ERK5 pathway by the IFNg receptor is required for IFNg-inducible antiviral responses
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ABSTRACT:
PROVIDER: PRJNA486768 | ENA |
REPOSITORIES: ENA
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Project description:Although well established that signal transducer and activator of transcription 1 (STAT1) activation is required for an interferon (IFN)-mediated antiviral response, the potential roles of other IFNg-activated cellular pathways in the process are unknown. We provide evidence that Unc-51-like kinase 1 (ULK1) is activated during engagement of the Type II IFN receptor and is required for IFNg-mediated transcription of key interferon stimulated genes involved in anti-viral and innate immune responses.
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Project description:Immune checkpoint inhibitors (ICIs) have transformed the treatment of melanoma. However, the majority of patients have primary or acquired resistance to ICIs, limiting durable responses and patient survival. Interferon-gamma (IFNg) signaling and the expression of IFNg-stimulated genes correlate with either response or resistance to ICIs, in a context-dependent manner. While IFNg-inducible immunostimulatory genes are required for response to ICIs, chronic IFNg signaling induces the expression of immunosuppressive genes, promoting resistance to these therapies. Here, we show that high levels of ULK1 correlate with poor survival in melanoma patients and overexpression of ULK1 in melanoma cells enhances IFNg-induced expression of immunosuppressive genes, with minimal effects on the expression of immunostimulatory genes. In contrast, genetic or pharmacological inhibition of ULK1 reduces expression of IFNg-induced immunosuppressive genes. ULK1 binds IRF1 in the nuclear compartment of melanoma cells, controlling its binding to the PD-L1 promoter region. Additionally, pharmacological inhibition of ULK1 in combination with anti-PD-1 therapy further reduces melanoma tumor growth and enhances anti-tumor immune responses in vivo. Our data suggest that targeting ULK1 represses IFNg-dependent immunosuppression. These findings support the combination of ULK1 drug-targeted inhibition with ICIs for the treatment of melanoma patients to improve response rates and patient outcomes.
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Project description:Activation of a novel ULK1-MLK3-ERK5 pathway by the IFNγ receptor is required for IFNγ-inducible antiviral responses
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Project description:The fruit fly Drosophila melanogaster is a good model to unravel the molecular mechanisms of innate immunity, and has led to some important discoveries on the sensing and signalling of microbial infections. The response of drosophila to virus infections remains poorly characterized, and appears to involve two facets. On one hand RNA interference (RNAi) involves the recognition and processing of dsRNA into small interfering (si) RNAs by the host ribonuclease Dicer-2 (Dcr-2), whereas on the other hand an inducible response controlled by the evolutionarily conserved JAK/STAT pathway contributes to the antiviral host defence. In order to clarify the contribution of the siRNA and JAK/STAT pathways to the control of viral infections, we have compared the resistance of flies wild-type or mutant for Dcr-2 or the JAK kinase Hopscotch (Hop) to infections by seven RNA or DNA viruses belonging to different families. Our results reveal a unique susceptibility of hop mutant flies to infection by DCV and CrPV, two members of the Dicistroviridae family. Genome-wide microarray analysis confirmed that different sets of genes were induced following infection by DCV (GSE2828) or two unrelated RNA viruses, FHV and SINV. Overall, our data reveal that RNAi is an efficient antiviral mechanism, operating against a large range of viruses, including a DNA virus. By contrast, the antiviral contribution of the JAK/STAT pathway appears to be virus-specific. For each experimental challenge (FHV, 48 or 72 hours after infection; SINV, 4 or 8 days after infection), three biologically independent samples composed of 45 male Oregon R flies were used. Infection has been performed by injecting viral stocks prepared in Tris solution. Injection of the same volume of Tris has been used as control. Infected flies were then incubated for 48 or 72 hours in the case of FHV and 4 days or 8 days in the case of SINV.
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