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

Ewa M. Kosciuczuk, Swarna Mehrotra, Diana Saleiro, Barbara Kroczynska, Beata Majchrzak-Kita, Pawel Lisowski, Caroline Driehaus, Anna Rogalska, Acara Turner, Thomas Lienhoop, David Gius, Eleanor N. Fish, Athanassios Vassilopoulos, Leonidas C. Platanias*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)827-837
Number of pages11
JournalJournal of Biological Chemistry
Volume294
Issue number3
DOIs
StatePublished - Jan 18 2019

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    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., & Platanias, L. C. (2019). Sirtuin 2–mediated deacetylation of cyclin-dependent kinase 9 promotes STAT1 signaling in type I interferon responses. Journal of Biological Chemistry, 294(3), 827-837. https://doi.org/10.1074/jbc.RA118.005956