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

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.

SUBMITTER: Kosciuczuk EM

PROVIDER: S-EPMC6341380 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Kosciuczuk Ewa M EM Mehrotra Swarna S Saleiro Diana D Kroczynska Barbara B Majchrzak-Kita Beata B Lisowski Pawel P Driehaus Caroline C Rogalska Anna A Turner Acara A Lienhoop Thomas T Gius David D Fish Eleanor N EN Vassilopoulos Athanassios A Platanias Leonidas C LC

The Journal of biological chemistry 20181128 3

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 ...[more]

PMID: 30487288

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Project description:Novel treatments for glioblastoma, the most common malignant primary brain tumor, are urgently required. Type I interferons (IFN) are natural cytokines primarily involved in the defense against viral infections, which may also serve a role in the control of cancer, notably in the suppression of the cancer stem cell phenotype. TG02 is a novel orally available cyclin-dependent kinase 9 inhibitor which induces glioma cell apoptosis without profound caspase activation, which is currently explored in early clinical trials in newly diagnosed and recurrent glioblastoma. In the present study, human glioma-initiating cell line models were used to explore whether IFN-? modulates the anti-glioma activity of TG02. The present study employed immunoblotting to assess protein levels, several viability assays and gene silencing strategies to assess gene function. Pre-exposure to IFN-? sensitized human glioma models to a subsequent exposure to TG02. Combination treatment was associated with increased DEVD-amc cleaving caspase activity that was blocked by the anti-apoptotic protein, BCL2. However, BCL2 did not protect from the synergistic effects of IFN and TG02 on glioma cell growth. Furthermore, although IFN strongly induced pro-apoptotic XIAP-associated factor (XAF) expression, disrupting XAF expression did not abrogate the synergy with TG02. Consistent with that, caspase 3 gene silencing did not abrogate the effects of TG02 or IFN-? alone or in combination. Finally, it was observed that IFN-? may indeed modulate the effects of TG02 upstream in the signaling cascade since inhibition of RNA polymerase II phosphorylation, a direct readout of the pharmacodynamic activity of TG02, was facilitated when glioma cells were pre-exposed to IFN-?. In summary, these data suggest that type I IFN may be combined with TG02 to limit glioblastoma growth, but that the well characterized effects of IFN and TG02 on apoptotic signaling are dispensable for synergistic tumor growth inhibition. Instead, exploring how IFN signaling primes glioma cells for TG02-mediated direct target inhibition may help to design novel and effective pharmacological approaches to glioblastoma.

Project description:Rotavirus (RV) replicates efficiently in intestinal epithelial cells (IECs) in vivo despite the activation of a local host interferon (IFN) response. Previously, we demonstrated that homologous RV efficiently inhibits IFN induction in single infected and bystander villous IECs in vivo. Paradoxically, RV also induces significant type I IFN expression in the intestinal hematopoietic cell compartment in a relatively replication-independent manner. This suggests that RV replication and spread in IECs must occur despite exogenous stimulation of the STAT1-mediated IFN signaling pathway. Here we report that RV inhibits IFN-mediated STAT1 tyrosine 701 phosphorylation in human IECs in vitro and identify RV NSP1 as a direct inhibitor of the pathway. Infection of human HT29 IECs with simian (RRV) or porcine (SB1A or OSU) RV strains, which inhibit IFN induction by targeting either IFN regulatory factor 3 (IRF3) or NF-?B, respectively, resulted in similar regulation of IFN secretion. By flow cytometric analysis at early times during infection, neither RRV nor SB1A effectively inhibited the activation of Y701-STAT1 in response to exogenously added IFN. However, at later times during infection, both RV strains efficiently inhibited IFN-mediated STAT1 activation within virus-infected cells, indicating that RV encodes inhibitors of IFN signaling targeting STAT1 phosphorylation. Expression of RV NSP1 in the absence of other viral proteins resulted in blockage of exogenous IFN-mediated STAT1 phosphorylation, and this function was conserved in NSP1 from simian, bovine, and murine RV strains. Analysis of NSP1 determinants responsible for the inhibition of IFN induction and signaling pathways revealed that these determinants are encoded on discrete domains of NSP1. Finally, we observed that at later times during infection with SB1A, there was almost complete inhibition of IFN-mediated Y701-STAT1 in bystander cells staining negative for viral antigen. This property segregated with the NSP1 gene and was observed in a simian SA11 monoreassortant that encoded porcine OSU NSP1 but not in wild-type SA11 or a reassortant encoding simian RRV NSP1.

Dataset Information

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

Publications

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

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