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Identification de mécanismes de régulation des fonctions des interférons: Rôle de la palmitoylation du récepteur de l'interféron de type I

Abstract : Type I interferons (IFNs) play key roles in mediating innate and acquired immune responses, in host defense against viral infections, and exhibit antiproliferative and tumoricidal activity. Through the binding to their shared cell surface receptor, composed of the two subunits IFNAR1 and IFNAR2, they induce the JAK/STAT signaling cascade, thus leading to their biological effects. The goal of my thesis was to identify regulatory mechanisms of IFNs signaling. In this context, we analyzed the role of protein palmitoylation, a lipid modification which is known to be involved in trafficking and signaling of proteins. We found that pharmacological inhibition of palmitoylation results in severe defects of IFN receptor endocytosis and signaling. We generated mutants of IFNAR1 where each or both of the two cysteines present in the cytoplasmic domain were replaced by alanines. We found that only Cys463, the most proximal of the two cytoplasmic cysteines, is palmitoylated. A thorough microscopic and biochemical analysis of the palmitoylation-deficient IFNAR1 mutant revealed that IFNAR1 palmitoylation is not required for receptor endocytosis, intracellular distribution, or stability at the cell surface. Nevertheless, the lack of IFNAR1 palmitoylation results in major defects in JAK/STAT signaling and gene transcription activated by IFN-a. Suprisingly, it had no effect on IFN-a antiproliferative activity, in spite of the importance of palmitoylation for signaling.
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https://tel.archives-ouvertes.fr/tel-00354695
Contributor : Julie Claudinon <>
Submitted on : Tuesday, January 20, 2009 - 3:58:02 PM
Last modification on : Thursday, December 10, 2020 - 10:50:39 AM
Long-term archiving on: : Tuesday, June 8, 2010 - 8:58:01 PM

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  • HAL Id : tel-00354695, version 1

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Julie Claudinon. Identification de mécanismes de régulation des fonctions des interférons: Rôle de la palmitoylation du récepteur de l'interféron de type I. Sciences du Vivant [q-bio]. Université Paris Sud - Paris XI, 2008. Français. ⟨tel-00354695⟩

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