Abstract
Type I interferons (IFNs) bind IFNAR receptors and activate Jak kinases and Stat transcription factors to stimulate the transcription of genes downstream from IFN-stimulated response elements. In this study, we analyze the role of protein palmitoylation, a reversible post-translational lipid modification, in the functional properties of IFNAR. We report that pharmacological inhibition of protein palmitoylation results in severe defects of IFN receptor endocytosis and signaling. We generated mutants of the IFNAR1 subunit of the type I IFN receptor, in which each or both of the two cysteines present in the cytoplasmic domain are replaced by alanines. We show that cysteine 463 of IFNAR1, the more 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. However, the lack of IFNAR1 palmitoylation affects selectively the activation of Stat2, which results in a lack of efficient Stat1 activation and nuclear translocation and IFN-alpha-activated gene transcription. Thus, receptor palmitoylation is a previously undescribed mechanism of regulating signaling activity by type I IFNs in the Jak/Stat pathway.
Highlights
Of many IFN-stimulated genes (ISGs) [1]
We report that IFNAR1 is palmitoylated on cysteine 463, and this modification has no major effect on IFNAR1 cellular trafficking, it strongly affects Janus tyrosine kinase (Jak)/signal-transducing activators of transcription (Stat) signaling and the gene transcription induced by IFN-␣
IFNAR1 Endocytosis and IFN-␣-induced Jak/Stat Signaling Depend on Palmitoylation Events—We recently showed that IFNAR1 uptake at the plasma membrane proceeds through classical clathrin- and dynamin-dependent endocytosis; inhibition of IFNAR1 endocytosis by either small interfering RNAmediated knockdown of clathrin or inactivation of the GTPase dynamin by the dominant negative mutant K44A inhibits both activation of the Jak/Stat signaling pathway and the antiviral and antiproliferative activities otherwise promoted by IFN-␣ [14]
Summary
Of many IFN-stimulated genes (ISGs) [1]. IFN signal transduction relies mainly on the activation of the Janus tyrosine kinase (Jak)/signal-transducing activators of transcription (Stat) pathways, several other signaling cascades have been associated with IFN-regulated transcription [2, 3]. Upon IFN-␣ stimulation, cytosolic Stat2 is recruited to the activated IFNAR complex where it becomes tyrosine-phosphorylated by the receptor-associated Jak kinases.
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