The innate immune response to infection represents the first cellular defense against invading pathogens. This response is orchestrated by a complex cohort of genes that are specifically induced upon infection and include cytokines, chemokines as well as other important antiviral mediators. While the function of many of these infectioninduced genes (and their antiviral activity) remains elusive, their regulated expression establishes an 'antiviral state' in the cell that is essential for the host defense to infections. Despite their protective role in infection, prolonged or aberrant expression of such genes can be deleterious to the host. As such, the expression of many antiviral mediators is strictly regulated, with subsets of genes expressed in distinct temporal patterns during infection. We plan here to characterize the function and mechanism of action of the putative helicase SETX, which is mutated in human patients with ataxia with oculomotor apraxia (AOA2) and a subset of Lou Gehrig's disease (ALS4). Our preliminary data using patientsderived SETX deficient cells indicate that SETX is a major player in controlling the antiviral response.
We aim at understanding through a multiscale analysis involving integrative proteomic and genomic approach the mechanism regulating SETX activity during infection.
Despite their protective role in infection, prolonged or aberrant expression of antiviral genes can be deleterious to the host. As such, the expression of many antiviral mediators is then strictly regulated, with subsets of genes expressed in distinct temporal patterns during infection. We used reporterbased assays coupled with chemical inhibitors of chromatin regulators to reveal a role for the helicase SETX in controlling the induction of antiviral genes. Using cuttingedge multiscale analysis we will study SETX regulation during infection, its mechanism of action, and the role during infection of SETX alleles that predispose to congenital defects like AOA2 and ALS4.
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