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Sirtuin 2-mediated deacetylation of cyclin-dependent kinase 9 promotes STAT1 signaling in type I interferon responses

Item Type:Article
Title:Sirtuin 2-mediated deacetylation of cyclin-dependent kinase 9 promotes STAT1 signaling in type I interferon responses
Creators Name:Kosciuczuk, E.M., Mehrotra, S., Saleiro, D., Kroczynska, B., Majchrzak-Kita, B., Lisowski, P., Driehaus, C., Rogalska, A., Turner, A., Lienhoop, T., Gius, D., Fish, E.N., Vassilopoulos, A. and Platanias, L.C.
Abstract:Type I interferons (IFNs) induce expression of multiple genes that control innate immune responses to invoke both antiviral and antineoplastic activities. Transcription of these interferon-stimulated genes (ISGs) occurs upon activation of the canonical Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathways. Phosphorylation and acetylation are both events crucial to tightly regulate expression of ISGs. Here, using mouse embryonic fibroblasts and an array of biochemical methods including immunoblotting and kinase assays, we show that sirtuin 2 (SIRT2), a member of the NAD-dependent protein deacetylase family, is involved in type I IFN signaling. We found that SIRT2, deacetylates cyclin-dependent kinase 9 (CDK9) in a type I IFN-dependent manner and that the CDK9 deacetylation is essential for STAT1 phosphorylation at Ser-727. We also found that SIRT2 is subsequently required for the transcription of ISGs and for IFN-driven antiproliferative responses in both normal and malignant cells. These findings establish the existence of a previously unreported signaling pathway whose function is essential for the control of JAK-STAT signaling and the regulation of IFN responses. Our findings suggest that targeting sirtuin activities may offer an avenue in the development of therapies for managing immune-related diseases and cancer.
Keywords:SIRT2, Type I IFN, Signal Transduction, STAT1, Deacetylation, Post-Translational Modification, Innate Immunity, HDAC, Cytokine, Immune Regulation, Animals, Mice
Source:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology
Page Range:827-837
Date:18 January 2019
Official Publication:https://doi.org/10.1074/jbc.RA118.005956
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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