Team 7 – MECHANISM OF INTERFERON ACTION AND BIOTHERAPEUTIC PATHWAYS

Our team has been working from many years on the mechanism of interferon (IFN) action. IFNs orchestrate the immune defense through the induction of hundreds of genes among which are the PML/TRIM19 and MX proteins. We have shown in different studies that PML, the organizer of nuclear bodies (NBs), is implicated in the antiviral response to diverse RNA viruses (VSV, rabies virus, poliovirus, EMCV, HFV, HIV-1). In addition to its intrinsic antiviral activity, one PML isoform (PMLIV) is implicated in innate immunity by positively regulating IFN-b synthesis. We also investigate the role of small ubiquitin-like modifier (SUMO) in intrinsic and innate immunity.

SUMO is involved in various cellular functions, including ubiquitin-mediated proteolysis, signal transduction, innate immunity and antiviral defense. We showed that the expression of SUMO leads to STAT1 SUMOylation and to a decrease in IFN-induced STAT1 phosphorylation which results in an inhibition of IFNγ-induced transcription without affecting that of IFNα. Our aim is to understand how the expression of SUMO renders cells resistant to some viruses and sensitive to others and to elucidate the role of SUMO on the IFN-stimulated gene products PKR and MX proteins. In addition, we will identify SUMOylated proteins in response to IFNs by using a proteomic approach that we have recently validated. The proteomic approach will allow the identification of all of the proteins modified with the different SUMO paralogs in response to IFN. Our approach may then contribute to the discovery of new key regulators of IFN.

 

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