Explore the vast range of titles available.

Key Points In the past decade, protein Lys acetylation has emerged as a major post-translational modification that occurs even in bacteria. This modification not only regulates chromatin-templated nuclear processes, but also controls classical metabolism, cytoskeleton dynamics, apoptosis, protein folding and cellular signalling in the cytoplasm. Lys deacetylases, the enzymes that are responsible for reversing this modification, are divided into the Rpd3/Hda1 (or classical) and sirtuin families, with the classical family having 11 members in mammals. These members are referred to as histone deacetylases (HDAC) 1–11. HDAC1, HDAC2 and HDAC3 are deacetylase subunits of multiprotein complexes that are crucial for chromatin modification and epigenetic landscaping. These complexes comprise subunits that are required for interplay with other chromatin modifications such as DNA and histone methylation, as well as with ATP-dependent chromatin remodelling. HDAC4, HDAC5, HDAC7 and HDAC9 are novel signal transducers that are tightly regulated by phosphorylation-dependent nucleocytoplasmic trafficking. Conceptually, they are similar to the cytokine-stimulated STAT and TGFβ-regulated SMAD signal-responsive transcription factors. By binding to ubiquitin and deacetylating α-tubulin, cortactin and HSP90, HDAC6 regulates various cytoplasmic processes including cytoskeleton dynamics, ciliogenesis, aggresome formation, autophagy, nuclear receptor maturation and, possibly, endocytosis of Tyr kinase receptors. HDAC inhibitors are promising therapeutic agents for cancer and other major diseases, as evidenced by the recent approval of one such inhibitor for the treatment of cutaneous T-cell lymphoma. The Rpd3/Hda1 family of protein lysine deacetylases has numerous substrates and diverse functions. Whereas class I enzymes are multiprotein histone deacetylase complexes that are crucial for chromatin modification and transcriptional regulation, some class II enzymes function as signal transducers that are regulated by nucleocytoplasmic translocation. Protein lysine deacetylases have a pivotal role in numerous biological processes and can be divided into the Rpd3/Hda1 and sirtuin families, each having members in diverse organisms including prokaryotes. In vertebrates, the Rpd3/Hda1 family contains 11 members, traditionally referred to as histone deacetylases (HDAC) 1–11, which are further grouped into classes I, II and IV. Whereas most class I HDACs are subunits of multiprotein nuclear complexes that are crucial for transcriptional repression and epigenetic landscaping, class II members regulate cytoplasmic processes or function as signal transducers that shuttle between the cytoplasm and the nucleus. Little is known about class IV HDAC11, although its evolutionary conservation implies a fundamental role in various organisms.

The smallest histone deacetylase (HDAC) and the only class IV HDAC member, HDAC11, is reported to regulate immune activation and tumorigenesis, yet its biochemical function is largely unknown. Here we identify HDAC11 as an efficient lysine defattyacylase that is >10,000-fold more efficient than its deacetylase activity. Through proteomics studies, we hypothesized and later biochemically validated SHMT2 as a defatty-acylation substrate of HDAC11. HDAC11-catalyzed defatty-acylation did not affect the enzymatic activity of SHMT2. Instead, it affects the ability of SHMT2 to regulate type I IFN receptor ubiquitination and cell surface level. Correspondingly, HDAC11 depletion increased type I IFN signaling in both cell culture and mice. This study not only demonstrates that HDAC11 has an activity that is much more efficient than the corresponding deacetylase activity, but also expands the physiological functions of HDAC11 and protein lysine fatty acylation, which opens up opportunities to develop HDAC11-specific inhibitors as therapeutics to modulate immune responses.

Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/protein deacetylase inhibitors (HDACi) may allow more titratable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models. Global HDAC11 deletion had no effect on health or development, and compared to WT controls, Foxp3+ Tregs lacking HDAC11 showed increased suppressive function, and increased expression of Foxp3 and TGF-β. Likewise, compared to WT recipients, conditional deletion of HDAC11 within Tregs led to long-term survival of fully MHC-mismatched cardiac allografts, and prevented development of transplant arteriosclerosis in an MHC class II-mismatched allograft model. The translational significance of HDAC11 targeting was shown by the ability of an HDAC11i to promote long-term allograft allografts in fully MHC-disparate strains. These data are powerful stimuli for the further development and testing of HDAC11-selective pharmacologic inhibitors, and may ultimately provide new therapies for transplantation and autoimmune diseases.

Histone deacetylases (HDACs) are conserved enzymes that regulate many cellular processes by catalyzing the removal of acetyl groups from lysine residues on histones and non-histone proteins. As appropriate for proteins that occupy such an essential biological role, HDAC activities and functions are in turn highly regulated. Overwhelming evidence suggests that the dysregulation of HDACs plays a major role in many human diseases. The regulation of HDACs is achieved by multiple different mechanisms, including posttranslational modifications. One of the most common posttranslational modifications on HDACs is reversible phosphorylation. Many HDAC phosphorylations are context-dependent, occurring in specific tissues or as a consequence of certain stimuli. Additionally, whereas phosphorylation can regulate some HDACs in a non-specific manner, many HDAC phosphorylations result in specific consequences. Although some of these modifications support normal HDAC function, aberrations can contribute to disease development. Here we review and critically evaluate how reversible phosphorylation activates or deactivates HDACs and, thereby, regulates their many functions under various cellular and physiological contexts.

Melanomas can adopt multiple transcriptional states. Little is known about the epigenetic drivers of these cell states, limiting our ability to regulate melanoma heterogeneity. Here, we identify stress-induced HDAC8 activity as driving melanoma brain metastasis development. Exposure of melanocytes and melanoma cells to multiple stresses increases HDAC8 activation leading to a neural crest-stem cell transcriptional state and an amoeboid, invasive phenotype that increases seeding to the brain. Using ATAC-Seq and ChIP-Seq we show that increased HDAC8 activity alters chromatin structure by increasing H3K27ac and enhancing accessibility at c-Jun binding sites. Functionally, HDAC8 deacetylates the histone acetyltransferase EP300, causing its enzymatic inactivation. This, in turn, increases binding of EP300 to Jun-transcriptional sites and decreases binding to MITF-transcriptional sites. Inhibition of EP300 increases melanoma cell invasion, resistance to stress and increases melanoma brain metastasis development. HDAC8 is identified as a mediator of transcriptional co-factor inactivation and chromatin accessibility that drives brain metastasis. The drivers of melanoma brain metastases (MBM) remain poorly understood. Here, the authors identify stress-induced HDAC8 activity as the driver of a neural crest-stem cell like transcriptional state that leads to MBM, and explore the molecular mechanism that drives this transition.

N-myristoylation on glycine is an irreversible modification that has long been recognized to govern protein localization and function. In contrast, the biological roles of lysine myristoylation remain ill-defined. We demonstrate that the cytoplasmic scaffolding protein, gravin-α/A kinase–anchoring protein 12, is myristoylated on two lysine residues embedded in its carboxyl-terminal protein kinase A (PKA) binding domain. Histone deacetylase 11 (HDAC11) docks to an adjacent region of gravin-α and demyristoylates these sites. In brown and white adipocytes, lysine myristoylation of gravin-α is required for signaling via β₂- and β₃-adrenergic receptors (β-ARs), which are G protein–coupled receptors (GPCRs). Lysine myristoylation of gravin-α drives β-ARs to lipid raft membrane microdomains, which results in PKA activation and downstream signaling that culminates in protective thermogenic gene expression. These findings define reversible lysine myristoylation as a mechanism for controlling GPCR signaling and highlight the potential of inhibiting HDAC11 to manipulate adipocyte phenotypes for therapeutic purposes.

Interleukin 10 dampens inflammation and prevents excessive tissue damage during immune responses. Sotomayor and colleagues show that the histone deacetylase HDAC11 negatively regulates expression of the gene encoding interleukin 10 and immune tolerance. Antigen-presenting cells (APCs) induce T cell activation as well as T cell tolerance. The molecular basis of the regulation of this critical 'decision' is not well understood. Here we show that HDAC11, a member of the HDAC histone deacetylase family with no prior defined physiological function, negatively regulated expression of the gene encoding interleukin 10 (IL-10) in APCs. Overexpression of HDAC11 inhibited IL-10 expression and induced inflammatory APCs that were able to prime naive T cells and restore the responsiveness of tolerant CD4 + T cells. Conversely, disruption of HDAC11 in APCs led to upregulation of expression of the gene encoding IL-10 and impairment of antigen-specific T cell responses. Thus, HDAC11 represents a molecular target that influences immune activation versus immune tolerance, a critical 'decision' with substantial implications in autoimmunity, transplantation and cancer immunotherapy.

Histone deacetylases (HDACs) deacetylate histones and non‐histone proteins, thereby affecting protein activity and gene expression. The regulation and function of the cytoplasmic class IIb HDAC6 in endothelial cells (ECs) is largely unexplored. Here, we demonstrate that HDAC6 is upregulated by hypoxia and is essential for angiogenesis. Silencing of HDAC6 in ECs decreases sprouting and migration in vitro and formation of functional vascular networks in matrigel plugs in vivo . HDAC6 regulates zebrafish vessel formation, and HDAC6‐deficient mice showed a reduced formation of perfused vessels in matrigel plugs. Consistently, overexpression of wild‐type HDAC6 increases sprouting from spheroids. HDAC6 function requires the catalytic activity but is independent of ubiquitin binding and deacetylation of α‐tubulin. Instead, we found that HDAC6 interacts with and deacetylates the actin‐remodelling protein cortactin in ECs, which is essential for zebrafish vessel formation and which mediates the angiogenic effect of HDAC6. In summary, we show that HDAC6 is necessary for angiogenesis in vivo and in vitro , involving the interaction and deacetylation of cortactin that regulates EC migration and sprouting. The histone deacetylase HDAC6 is essential for endothelial cell sprouting and migration, and hence the formation of functional vascular networks in zebrafish and mouse. HDAC6 regulates angiogenesis through deacetylation of the actin‐remodelling protein cortactin.

HDAC1 is the prototypical human histone deacetylase (HDAC) enzyme responsible for catalyzing the removal of acetyl group from lysine residues on many substrate proteins. By deacetylating histones and non-histone proteins, HDAC1 has a profound effect on the regulation of gene transcription and many processes related to cell growth and cell death, including cell cycle progression, DNA repair, and apoptosis. Early studies reveal that, like most eukaryotic proteins, the functions and activities of HDAC1 are regulated by post-translational modifications. For example, serine phosphorylation of HDAC1 by protein kinase CK2 promotes HDAC1 deacetylase enzymatic activity and alters its interactions with proteins in corepressor complexes. Here, we describe an alternative signaling pathway by which HDAC1 activities are regulated. Specifically, we discover that EGFR activity promotes the tyrosine phosphorylation of HDAC1, which is necessary for its protein stability. A key EGFR phosphorylation site on HDAC1, Tyr72, mediates HDAC1’s anti-apoptotic function. Given that HDAC1 overexpression and EGFR activity are strongly related with tumor progression and cancer cell survival, HDAC1 tyrosine phosphorylation may present a possible target to manipulate HDAC1 protein levels in future potential cancer treatment strategies.

Histone deacetylase 6 （HDAC6）, a predominantly cyto- plasmic protein deacetylase, participates in a wide range of cellular processes through its deacetylase activity. However, the diverse functions of HDAC6 can- not be fully elucidated with its known substrates. In an attempt to explore the substrate diversity of HDAC6, we performed quantitative proteomic analyses to monitor changes in the abundance of protein lysine acetylation in response to HDAC6 deficiency. We identified 107 proteins with elevated acetylation in the liver of HDAC6 knockout mice. Three cytoplasmic proteins, including myosin heavy chain 9 （MYH9）, heat shock cognate pro- tein 70 （HscT0）, and dnaJ homolog subfamily A member 1 （DNAJA1）, were verified to interact with HDAC6. The acetylation levels of these proteins were negatively regulated by HDAC6 both in the mouse liver and in cultured cells. Functional studies reveal that HDAC6- mediated deacetylation modulates the actin-binding ability of MYH9 and the interaction between Hsc70 and DNAJA1. These findings consolidate the notion that HDAC6 serves as a critical regulator of proteinacetylation with the capability of coordinating various cellular functions.