New insights into the non-enzymatic function of HDAC6

Zhu, Yuan-Zai; Feng, Mengkai; Wang, Bo; Zheng, Yi-Chao; Jiang, Dandan; Zhao, Lijuan; Mamun, M. A. A.; Kang, Huifang; Nie, Hai-Qian; Zhang, Xiya; Guo, Ningjie; Qin, Shangshang; Wang, Ning; Liu, Hong‐Min; Gao, Ya

doi:10.1016/j.biopha.2023.114438

Cited by 13 publications

(9 citation statements)

References 123 publications

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“…80,81 A relocalization requirement likely explains why partial, but not complete, defects in inflammasome activity are caused by defects in the dynein adapter histone deacetylase 6 (HDAC6), HDAC6 inhibitors, defects in microtubule-affinity reducing kinase 4 (MARK4), dynein disruption, and loss of the aggresome component vimentin. 77,[82][83][84][85][86][87][88][89][90][91] Cargo recruited for transport by HDAC6 is typically ubiquitinated, 92 and extensive studies have indicated that NLRP3 inflammasome components are regulated both positively and negatively by ubiquitination. 93 A relocalization requirement also explains why the microtubule depolymerizing agent colchicine is useful in treating symptoms of gout, which is an NLRP3-mediated disease; colchicine sodium urea crystals.…”

Section: F I G U R Ementioning

confidence: 99%

The discovery of NLRP3 and its function in cryopyrin‐associated periodic syndromes and innate immunity

Putnam,

Broderick,

Hoffman

2023

Immunological Reviews

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SummaryFrom studies of individual families to global collaborative efforts, the NLRP3 inflammasome is now recognized to be a key regulator of innate immunity. Activated by a panoply of pathogen‐associated and endogenous triggers, NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL‐1 and IL‐18. Initially discovered as the cause of the autoinflammatory spectrum of cryopyrin‐associated periodic syndrome (CAPS), NLRP3 is now also known to play a role in more common diseases including cardiovascular disease, gout, and liver disease. We have seen cohesion in results from clinical studies in CAPS patients, ex vivo studies of human cells and murine cells, and in vivo murine models leading to our understanding of the downstream pathways, cytokine secretion, and cell death pathways that has solidified the role of autoinflammation in the pathogenesis of human disease. Recent advances in our understanding of the structure of the inflammasome have provided ways for us to visualize normal and mutant protein function and pharmacologic inhibition. The subsequent development of targeted therapies successfully used in the treatment of patients with CAPS completes the bench to bedside translational loop which has defined the study of this unique protein.

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Section: F I G U R Ementioning

confidence: 99%

The discovery of NLRP3 and its function in cryopyrin‐associated periodic syndromes and innate immunity

Putnam,

Broderick,

Hoffman

2023

Immunological Reviews

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“…binding domain. 25,26 This domain is reported to be involved in the recruitment of polyubiquitinated misfolded proteins to dynein motors for transport to aggresomes. 27−29 Selectivity over other HDACs, especially class I (HDAC1−3 and 8), is expected to be required to avoid the risk of safety issues in the development of an HDAC6 inhibitor for the treatment of respiratory diseases.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Both domains may be required for catalytic activity and a possible function of CD1 is to serve as a microtubule-binding domain . HDAC6 is also unique among the isoforms, in that it contains a C-terminal ubiquitin-binding domain. , This domain is reported to be involved in the recruitment of polyubiquitinated misfolded proteins to dynein motors for transport to aggresomes. − Selectivity over other HDACs, especially class I (HDAC1–3 and 8), is expected to be required to avoid the risk of safety issues in the development of an HDAC6 inhibitor for the treatment of respiratory diseases.…”

Section: Introductionmentioning

confidence: 99%

Selective and Bioavailable HDAC6 2-(Difluoromethyl)-1,3,4-oxadiazole Substrate Inhibitors and Modeling of Their Bioactivation Mechanism

Ripa,

Sandmark,

Hughes

et al. 2023

J. Med. Chem.

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Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family mainly targeting cytosolic nonhistone substrates, such as α-tubulin, cortactin, and heat shock protein 90 to regulate cell proliferation, metastasis, invasion, and mitosis in tumors. We describe the identification and characterization of a series of 2-(difluoromethyl)-1,3,4-oxadiazoles (DFMOs) as selective nonhydroxamic acid HDAC6 inhibitors. By comparing structure–activity relationships and performing quantum mechanical calculations of the HDAC6 catalytic mechanism, we show that potent oxadiazoles are electrophilic substrates of HDAC6 and propose a mechanism for the bioactivation. We also observe that the inherent electrophilicity of the oxadiazoles makes them prone to degradation in water solution and the generation of potentially toxic products cannot be ruled out, limiting the developability for chronic diseases. However, the oxadiazoles demonstrate high oral bioavailability and low in vivo clearance and are excellent tools for studying the role of HDAC6 in vitro and in vivo in rats and mice.

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“…[11,12] These characteristics enable HDAC6 to control a wide range of biological functions, such as clearance of misfolded protein by degradation, immunological response, cell migration, cell proliferation, and neurological changes. [13,14] In recent years, there has been keen interest in establishing the relationship between HDAC6 and AD. Several studies have discovered an elevated expression of HDAC6 in the brains of AD patients, [15] which results in lowering acetylated 𝛼-tubulin levels that eventually cause dysfunctional neurons.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure‐Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology

Mondal,

Bai,

Gomm

et al. 2023

Advanced Science

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Histone deacetylase 6 (HDAC6) is one of the key histone deacetylases (HDACs) that regulates various cellular functions including clearance of misfolded protein and immunological responses. Considerable evidence suggests that HDAC6 is closely related to amyloid and tau pathology, the two primary hallmarks of Alzheimer's disease (AD). It is still unclear whether HDAC6 expression changes with amyloid deposition in AD during disease progression or HDAC6 may be regulating amyloid phagocytosis or neuroinflammation or other neuropathological changes in AD. In this work, the pathological accumulation of HDAC6 in AD brains over age as well as the relationship of its regulatory activity ‐ with amyloid pathogenesis and pathophysiological alterations is aimed to be enlightened using the newly developed HDAC6 inhibitor (HDAC6i) PB118 in microglia BV2 cell and 3D‐AD human neural culture model. Results suggest that the structure‐based rational design led to biologically compelling HDAC6i PB118 with multiple mechanisms that clear Aβ deposits by upregulating phagocytosis, improve tubulin/microtubule network by enhancing acetyl α‐tubulin levels, regulate different cytokines and chemokines responsible for inflammation, and significantly reduce phospho‐tau (p‐tau) levels associated with AD. These findings indicate that HDAC6 plays key roles in the pathophysiology of AD and potentially serves as a suitable pharmacological target through chemical biology‐based drug discovery in AD.

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New insights into the non-enzymatic function of HDAC6

Cited by 13 publications

References 123 publications

The discovery of NLRP3 and its function in cryopyrin‐associated periodic syndromes and innate immunity

The discovery of NLRP3 and its function in cryopyrin‐associated periodic syndromes and innate immunity

Selective and Bioavailable HDAC6 2-(Difluoromethyl)-1,3,4-oxadiazole Substrate Inhibitors and Modeling of Their Bioactivation Mechanism

Structure‐Based Discovery of A Small Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) that Significantly Reduces Alzheimer's Disease Neuropathology

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