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

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

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 1 2019

Fingerprint

Cyclin-Dependent Kinase 9
Interferon Type I
Sirtuin 2
Interferons
Transcription
Genes
Phosphorylation
Janus Kinases
Acetylation
Immune System Diseases
Fibroblasts
Transducers
Immunoblotting
Innate Immunity
Antineoplastic Agents
NAD
Antiviral Agents
Assays
Phosphotransferases
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kosciuczuk, Ewa M. ; Mehrotra, Swarna ; Nora Vaz Saleiro, Diana ; Kroczynska, Barbara ; Majchrzak-Kita, Beata ; Lisowski, Pawel ; Driehaus, Caroline ; Rogalska, Anna ; Turner, Acara ; Lienhoop, Thomas ; Gius, David R ; Fish, Eleanor N. ; Vasilopoulos, Athanasios ; Platanias, Leonidas C. / Sirtuin 2–mediated deacetylation of cyclin-dependent kinase 9 promotes STAT1 signaling in type I interferon responses. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 3. pp. 827-837.
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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.",
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Kosciuczuk, EM, Mehrotra, S, Nora Vaz Saleiro, D, Kroczynska, B, Majchrzak-Kita, B, Lisowski, P, Driehaus, C, Rogalska, A, Turner, A, Lienhoop, T, Gius, DR, Fish, EN, Vasilopoulos, A & Platanias, LC 2019, 'Sirtuin 2–mediated deacetylation of cyclin-dependent kinase 9 promotes STAT1 signaling in type I interferon responses', Journal of Biological Chemistry, vol. 294, no. 3, pp. 827-837. https://doi.org/10.1074/jbc.RA118.005956

Sirtuin 2–mediated deacetylation of cyclin-dependent kinase 9 promotes STAT1 signaling in type I interferon responses. / Kosciuczuk, Ewa M.; Mehrotra, Swarna; Nora Vaz Saleiro, Diana; Kroczynska, Barbara; Majchrzak-Kita, Beata; Lisowski, Pawel; Driehaus, Caroline; Rogalska, Anna; Turner, Acara; Lienhoop, Thomas; Gius, David R; Fish, Eleanor N.; Vasilopoulos, Athanasios; Platanias, Leonidas C.

In: Journal of Biological Chemistry, Vol. 294, No. 3, 01.01.2019, p. 827-837.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Sirtuin 2–mediated deacetylation of cyclin-dependent kinase 9 promotes STAT1 signaling in type I interferon responses

AU - Kosciuczuk, Ewa M.

AU - Mehrotra, Swarna

AU - Nora Vaz Saleiro, Diana

AU - Kroczynska, Barbara

AU - Majchrzak-Kita, Beata

AU - Lisowski, Pawel

AU - Driehaus, Caroline

AU - Rogalska, Anna

AU - Turner, Acara

AU - Lienhoop, Thomas

AU - Gius, David R

AU - Fish, Eleanor N.

AU - Vasilopoulos, Athanasios

AU - Platanias, Leonidas C

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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