Histone deacetylase | EPFL Graph Search

Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. HDAC super family Together with the acetylpolyamine amidohydrolases and the acetoin utilization proteins, the histone deacetylases form an ancient protein superfamily known as the histone deacetylase superfamily. Classes of HDACs in higher eukaryotes HDACs, are classified in four classes depending on sequence homology to the yeast original enzymes and domain organization: HDAC (except class III) contain z

Class I histone deacetylases (HDAC1-3) are histone lysine delactylases

Alexander Lund Nielsen, Di Zhang

Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with functions that are different from the widely studied histone acetylation. While K(L-la) can be introduced by the acetyltransferase p300, histone delactylases enzymes remained unknown. Here, we report the systematic evaluation of zinc- and nicotinamide adenine dinucleotide-dependent histone deacetylases (HDACs) for their ability to cleave epsilon-N-L-lactyllysine marks. Our screens identified HDAC1-3 and SIRT1-3 as delactylases in vitro. HDAC1-3 show robust activity toward not only K(L-la) but also K(D-la) and diverse short-chain acyl modifications. We further confirmed the de-L-lactylase activity of HDACs 1 and 3 in cells. Together, these data suggest that histone lactylation is installed and removed by regulatory enzymes as opposed to spontaneous chemical reactivity. Our results therefore represent an important step toward full characterization of this pathway's regulatory elements.

2022

Sirtuin 2 Deficiency Increases Bacterial Phagocytosis by Macrophages and Protects from Chronic Staphylococcal Infection

Johan Auwerx, Tytti Heinonen, Marc Pfefferlé

Sirtuin 2 (SIRT2) is one of the seven members of the family of NAD(+)-dependent histone deacetylases. Sirtuins target histones and non-histone proteins according to their subcellular localization, influencing various biological processes. SIRT2 resides mainly in the cytoplasm and regulates cytoskeleton dynamics, cell cycle, and metabolic pathways. As such, SIRT2 has been implicated in the pathogenesis of neurodegenerative, metabolic, oncologic, and chronic inflammatory disorders. This motivated the development of SIRT2-directed therapies for clinical purposes. However, the impact of SIRT2 on antimicrobial host defense is largely unknown. Here, we address this question using SIRT2 knockout mice. We show that SIRT2 is the most highly expressed sirtuin in myeloid cells, especially macrophages. SIRT2 deficiency does not affect immune cell development and marginally impacts on intracellular signaling and cytokine production by splenocytes and macrophages. However, SIRT2 deficiency enhances bacterial phagocytosis by macrophages. In line with these observations, in preclinical models, SIRT2 deficiency increases survival of mice with chronic staphylococcal infection, while having no effect on the course of toxic shock syndrome toxin-1, LPS or TNF-induced shock, fulminant Escherichia coli peritonitis, sub-lethal Klebsiella pneumoniae pneumonia, and chronic candidiasis. Altogether, these data support the safety profile of SIRT2 inhibitors under clinical development in terms of susceptibility to infections.

Frontiers Media Sa2017

The role of nicotinamide riboside metabolism in pancreatic beta cells

Angélique Satoko Cercillieux

Pancreatic beta cells play a major role in the regulation of glucose homeostasis by secreting insulin in response to elevated blood glucose levels. A gradual deterioration of functional beta cell mass and the chronic elevation of blood glucose levels are central to development of type 2 diabetes. While the etiologies of Type 2 diabetes and age-related metabolic complications are complex, they are often associated with a decline of intracellular nicotinamide adenine dinucleotide (NAD+). NAD+ levels are maintained through the balance between its synthesis from NAD+ precursors and its degradation by several families of enzymes, including the sirtuin family of protein deacetylases, the ADP-ribosyl transferase enzymes (ARTDs or PARPs) and cADP ribose hydrolases (CD38). NAD+ declines are mostly associated with increased NAD+ consumption, which can be counteracted by dietary supplementation of NAD+ precursors. However, our knowledge on how different tissues utilize and respond to different NAD+ precursors for NAD+ synthesis is still incomplete. This, in turn, limits our ability to provide therapeutic benefits in clinical settings. In this project, we aim to understand the relevance of a particular NAD+ precursor, nicotinamide riboside (NR), in beta cell physiology and its potential use to treat beta cell dysfunction. To do so, we have used mice that are deficient for nicotinamide riboside kinase 1 (NRK1), the first and rate-limiting enzyme for the transformation of NR into NAD+. We demonstrate that NRK1 whole body knockout mice exhibit impaired insulin secretion after a meal or upon glucose challenge when fed a high fat diet. However, NRK1 deficiency in beta cell was not the causality for beta cell failure as differences observed in the NRK1 whole body KO mice were not phenocopied in NRK1 beta cell specific KO mice. Aged NRK1 whole body KO mice also exhibited dysfunctional beta cells and significant loss of insulin content and beta cell mass. Furthermore, NRK1 deficiency exacerbates the decline of NAD+ bioavailability and mitochondria function with age, even promoting fibrosis in multiple tissues. Together, our data suggests that endogenous NR metabolism is critical in maintaining whole body NAD+ homeostasis and to protect against mitochondria dysfunction and stress-related cell responses in pancreatic beta cells.

EPFL2022

The role of nicotinamide riboside metabolism in pancreatic beta cells

Angélique Satoko Cercillieux

EPFL2022