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SIRT1 negatively regulates the activities, functions, and protein levels of hMOF and TIP60.

ABSTRACT: SIRT1 is a NAD(+)-dependent histone H4K16 deacetylase that controls several different normal physiologic and disease processes. Like most histone deacetylases, SIRT1 also deacetylates nonhistone proteins. Here, we show that two members of the MYST (MOZ, Ybf2/Sas3, Sas2, and TIP60) acetyltransferase family, hMOF and TIP60, are SIRT1 substrates. SIRT1 deacetylation of the enzymatic domains of hMOF and TIP60 inhibits their acetyltransferase activity and promotes ubiquitination-dependent degradation of these proteins. Importantly, immediately following DNA damage, the binding of SIRT1 to hMOF and TIP60 is transiently interrupted, with corresponding hMOF/TIP60 hyperacetylation. Lysine-to-arginine mutations in SIRT1-targeted lysines on hMOF and TIP60 repress DNA double-strand break repair and inhibit the ability of hMOF/TIP60 to induce apoptosis in response to DNA double-strand break. Together, these findings uncover novel pathways in which SIRT1 dynamically interacts with and regulates hMOF and TIP60 through deacetylation and provide additional mechanistic insights by which SIRT1 regulates DNA damage response.

SUBMITTER: Peng L

PROVIDER: S-EPMC3416197 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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SIRT1 negatively regulates the activities, functions, and protein levels of hMOF and TIP60.

Peng Lirong L Ling Hongbo H Yuan Zhigang Z Fang Bin B Bloom Gregory G Fukasawa Kenji K Koomen John J Chen Jiandong J Lane William S WS Seto Edward E

Molecular and cellular biology 20120514 14

SIRT1 is a NAD(+)-dependent histone H4K16 deacetylase that controls several different normal physiologic and disease processes. Like most histone deacetylases, SIRT1 also deacetylates nonhistone proteins. Here, we show that two members of the MYST (MOZ, Ybf2/Sas3, Sas2, and TIP60) acetyltransferase family, hMOF and TIP60, are SIRT1 substrates. SIRT1 deacetylation of the enzymatic domains of hMOF and TIP60 inhibits their acetyltransferase activity and promotes ubiquitination-dependent degradation ...[more]

PMID: 22586264

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Project description:Interferon-inducible protein 16 (IFI16) plays a critical role in antiviral innate immune responses against DNA viruses. Although the acetylation of IFI16 is crucial to its cytoplasmic translocation and downstream signal transduction, the regulation of IFI16 acetylation remains unclear. In this study, we demonstrated that the NAD-dependent deacetylase silent information regulatory 1 (Sirtuin1, Sirt1) interacted with IFI16 and decreased the acetylation of IFI16, resulting in the inhibition of IFI16 cytoplasmic localization and antiviral responses against DNA virus and viral DNA in human cells. Meantime, Sirt1 could not inhibit RNA virus-triggered signal transduction. Interestingly, even p204, the murine ortholog of human IFI16, barely interacted with Sirt1. Thus, Sirt1 could not negatively regulate the acetylation of p204 and subsequent signal transduction upon herpes simplex virus 1 (HSV-1) infection in mouse cells. Taken together, our research work showed a new mechanism by which Sirt1 manipulated IFI16-mediated host defense. Our study also demonstrated a difference in the regulation of antiviral host defense between humans and mice, which might be considered in preclinical studies for antiviral treatment. IMPORTANCE DNA viruses, such as hepatitis B virus (HBV), human papillomavirus (HPV), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and herpes simplex virus (HSV), can cause a wide range of diseases and are considered a global threat to human health. Interferon-inducible protein 16 (IFI16) binds virus DNA and triggers antiviral innate immune responses to restrict viral infection. In this study, we identified that silent information regulatory 1 (Sirtuin1, Sirt1) interacted with IFI16 and regulated IFI16-mediated innate host defense. Therefore, the activator or inhibitor of Sirt1 may have the potential to be used as a novel strategy to treat DNA virus-associated diseases. We also found that Sirt1 barely interacted with p204, the murine ortholog of human IFI16, and could not negatively regulate innate immune responses upon HSV-1 infection in mouse cells. This difference between humans and mice in the regulation of antiviral host defense might be considered in preclinical studies for antiviral treatment.

Dataset Information

SIRT1 negatively regulates the activities, functions, and protein levels of hMOF and TIP60.

Publications

SIRT1 negatively regulates the activities, functions, and protein levels of hMOF and TIP60.

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