HDAC6 at Crossroads of Infection and Innate Immunity

Moreno-Gonzalo, Olga; Mayor, Federico; Sánchez-Madrid, Francisco

doi:10.1016/j.it.2018.05.004

Cited by 33 publications

(30 citation statements)

References 14 publications

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“…Additionally, HDAC6 inhibition significantly decreases M2-like macrophages ( Knox et al, 2019 ; Banik et al, 2020 ), thus suggesting that HDAC6 inhibitors could be used to decrease M2-like macrophage-driven fibroblast activation. Besides, HDAC6 plays an essential role in viral entry ( Banerjee et al, 2014 ) and innate immunity ( Moreno-Gonzalo et al, 2018 ). Although epigenetic modifiers are not in clinical trials for COVID-19 patients at the moment of writing this review, they represent an attractive approach as they can regulate multiple cellular processes.…”

Section: Therapeutic Targeting Of Macrophage-induced Complications Inmentioning

confidence: 99%

Targeting Macrophages as a Therapeutic Option in Coronavirus Disease 2019

2020

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Immune cells of the monocyte/macrophage lineage are characterized by their diversity, plasticity, and variety of functions. Among them, macrophages play a central role in antiviral responses, tissue repair, and fibrosis. Macrophages can be reprogrammed by environmental cues, thus changing their phenotype during an antiviral immune response as the viral infection progresses. While M1-like macrophages are essential for the initial inflammatory responses, M2-like macrophages are critical for tissue repair after pathogen clearance. Numerous reports have evaluated the detrimental effects that coronaviruses, e.g., HCoV-229E, SARS-CoV, MERS-CoV, and SARS-CoV-2, have on the antiviral immune response and macrophage functions. In this review, we have addressed the breadth of macrophage phenotypes during the antiviral response and provided an overview of macrophage-coronavirus interactions. We also discussed therapeutic approaches to target macrophage-induced complications, currently under evaluation in clinical trials for coronavirus disease 2019 patients. Additionally, we have proposed alternative approaches that target macrophage recruitment, interferon signaling, cytokine storm, pulmonary fibrosis, and hypercoagulability.

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Section: Therapeutic Targeting Of Macrophage-induced Complications Inmentioning

confidence: 99%

Targeting Macrophages as a Therapeutic Option in Coronavirus Disease 2019

2020

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“…HDAC6-mediated deacetylation reduces microtubule stability and impairs kinesin and dynein-dependent transport of various cargoes, and such movement mechanisms are co-opted by pathogens, including viruses and intracellular bacteria [181–183]. HDAC6 has also been related to the regulation of viral fusion, entry, nuclear trafficking, replication, assembly, and egress [182]. Interestingly, GRK2 has been shown to support infection of several flaviviruses, such as yellow fever virus (YFV), dengue virus (DENV), and Hepatitis C virus (HCV) [184], and a recent report using quantitative phosphoproteomics in A549 human lung epithelial cells indicates that GRK2 is crucially involved in the initial steps of Influenza A virus (IAV) infection [185].…”

Section: Examples Of Context-specific Grk2 Multifunctionalitymentioning

confidence: 99%

G protein-coupled receptor kinase 2 (GRK2) as a multifunctional signaling hub

Penela

Ribas

Sánchez-Madrid

et al. 2019

Cell. Mol. Life Sci.

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Accumulating evidence indicates that G protein-coupled receptor kinase 2 (GRK2) is a versatile protein that acts as a signaling hub by modulating G protein-coupled receptor (GPCR) signaling and also via phosphorylation or scaffolding interactions with an extensive number of non-GPCR cellular partners. GRK2 multifunctionality arises from its multidomain structure and from complex mechanisms of regulation of its expression levels, activity, and localization within the cell, what allows the precise spatio-temporal shaping of GRK2 targets. A better understanding of the GRK2 interactome and its modulation mechanisms is helping to identify the GRK2-interacting proteins and its substrates involved in the participation of this kinase in different cellular processes and pathophysiological contexts.

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“…Mechanistically, we hypothesize that histone deacetylase 6 (HDAC6) inhibition would benefit behavioral changes associated with CF. HDAC6 is a member of a ubiquitous, large family of enzymes that remove acetyl groups from lysine residues in proteins and acts on non-histone proteins including alpha tubulin 18 . We have shown slower microtubule reformation rates, as well as decreased acetylated microtubule levels in CF cells and tissues indicating inherent changes to microtubule regulation in the absence of CFTR 19 – 21 .…”

Section: Introductionmentioning

confidence: 99%

Alleviation of depression-like behavior in a cystic fibrosis mouse model by Hdac6 depletion

Corey

Rymut

Kelley

2020

Sci Rep

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Cystic fibrosis (CF) patients experience heightened levels of anxiety and depression. Stress from dealing with chronic disease and rigorous treatment regimens certainly are primary contributors to these outcomes. We previously have demonstrated that microtubule alterations in CF are linked to a number of CF phenotypes including growth regulation and inflammatory responses to airway bacterial challenge. Deletion of histone deactelyase 6 (HDAC6), a cytosolic deacetylase that regulates tubulin acetylation, in CF mice restores growth and inflammatory phenotypes to wild type (WT) profiles. In this study, the hypothesis that Hdac6 depletion in CF mice would impact behaviors since Hda6 inhibition has been previously reported to have anti-depressive properties. Data demonstrate that CF mice exhibit reduced activity and reduced open arm time in an elevated plus maze test which can be consistent with anxiety-like behavior. CF mice also exhibit depression-like behaviors compared to WT mice in an age dependent manner. By eight weeks of age, CF mice exhibit significantly more immobile time in the tail-suspension test, however, Hdac6 depletion reverses the depressive phenotype. These data demonstrate that loss of CFTR function may predispose patients to experience depression and that this behavior is Hdac6 dependent.

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HDAC6 at Crossroads of Infection and Innate Immunity

Cited by 33 publications

References 14 publications

Targeting Macrophages as a Therapeutic Option in Coronavirus Disease 2019

Targeting Macrophages as a Therapeutic Option in Coronavirus Disease 2019

G protein-coupled receptor kinase 2 (GRK2) as a multifunctional signaling hub

Alleviation of depression-like behavior in a cystic fibrosis mouse model by Hdac6 depletion

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