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. cro ARTICLE

CDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci

“…Previous studies have described CDKs as regulators of STAT1 Ser phosphorylation in different systems (Bancerek et al, 2013;Chen et al, 2019;Kosciuczuk et al, 2019;Putz et al, 2013). Thus, we next tested whether the STAT3 Ser phosphorylation induced by HyIL-6 was mediated by CDKs.…”

Gestation and breastfeeding in schistosomotic mice differentially alters the expression of histone deacetylases (HDACs) in adult offspring

“…It is known that Sirt2 acts on the anti-inflammatory pathway in M2 macrophages through expression of Arginase 1 (Arg1) and Cd11c, (21) and reduces ROS by increasing superoxide dismutase 2 (SOD2), catalase, and glutathione peroxidase. (8) The increase in Sirt2 was related to inhibition of the NF-κβ pathway and reduced expression of IL-1β, IL-6, and TNF-α. (21) Sirt7 acts on the stabilisation of TGF-β receptor type 1, allowing for efficient signalling of TGF-β.…”

“…Prior exposure to the breast milk of schistosomotic mothers positively altered the expression of HDACs from different classes linked to reduction and/or resolution of the inflammatory response. (8,20,21) There was an increase in the relative expression of HDACs 1, 2 and 7, all of which show anti-inflammatory activity by inhibiting the transcription of NF-κβ and decreasing the production of inflammatory cytokines (TNF-α, IL-1, IL-6). (7,22,23) There was a decrease in HDAC3 expression in all experimental groups (at baseline), but this recovered to levels similar to Control in response to mitogen.…”

“…Studies have correlated post-transcriptional changes in the chromatin, through histone acetylation/deacetylation, with the immune response. (6,7,8) In an experimental study on antigen presenting cells (APCs), it was demonstrated that histone deacetylase (HDAC)6 is required for transcriptional activation of IL-10 gene expression in macrophages and dendritic cells through activation of STAT3. (6) Another study using pancreatic beta cell lines showed that knockdown of HDAC1 increased IFN-γinduced STAT1 phosphorylation.…”

“…(6) Another study using pancreatic beta cell lines showed that knockdown of HDAC1 increased IFN-γinduced STAT1 phosphorylation. (7) Kosciuczuk et al (8) showed that deacetylation of cyclin-dependent kinase 9 induced by Sirtuin 2 promotes STAT1 phosphorylation during type I interferon responses.…”