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  1. Article ; Online: CFTR is required for zinc-mediated antibacterial defense in human macrophages.

    Das Gupta, Kaustav / Curson, James E B / Tarique, Abdullah A / Kapetanovic, Ronan / Schembri, Mark A / Fantino, Emmanuelle / Sly, Peter D / Sweet, Matthew J

    Proceedings of the National Academy of Sciences of the United States of America

    2024  Volume 121, Issue 8, Page(s) e2315190121

    Abstract: Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion transporter required for epithelial homeostasis in the lung and other organs, ... ...

    Abstract Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion transporter required for epithelial homeostasis in the lung and other organs, with
    MeSH term(s) Humans ; Anti-Bacterial Agents/therapeutic use ; Cystic Fibrosis/microbiology ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Macrophages/metabolism ; Macrophages/microbiology ; Zinc/metabolism
    Chemical Substances Anti-Bacterial Agents ; CFTR protein, human ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; Zinc (J41CSQ7QDS)
    Language English
    Publishing date 2024-02-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2315190121
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  2. Article ; Online: TLR4 phosphorylation at tyrosine 672 activates the ERK/c-FOS signaling module for LPS-induced cytokine responses in macrophages.

    Curson, James E B / Liu, Liping / Luo, Lin / Muusse, Timothy W / Lucas, Richard M / Gunther, Kimberley S / Vajjhala, Parimala R / Abrol, Rishika / Jones, Alun / Kapetanovic, Ronan / Stacey, Katryn J / Stow, Jennifer L / Sweet, Matthew J

    European journal of immunology

    2023  Volume 53, Issue 7, Page(s) e2250056

    Abstract: TLRs engage numerous adaptor proteins and signaling molecules, enabling a complex series of post-translational modifications (PTMs) to mount inflammatory responses. TLRs themselves are post-translationally modified following ligand-induced activation, ... ...

    Abstract TLRs engage numerous adaptor proteins and signaling molecules, enabling a complex series of post-translational modifications (PTMs) to mount inflammatory responses. TLRs themselves are post-translationally modified following ligand-induced activation, with this being required to relay the full spectrum of proinflammatory signaling responses. Here, we reveal indispensable roles for TLR4 Y672 and Y749 phosphorylation in mounting optimal LPS-inducible inflammatory responses in primary mouse macrophages. LPS promotes phosphorylation at both tyrosine residues, with Y749 phosphorylation being required for maintenance of total TLR4 protein levels and Y672 phosphorylation exerting its pro-inflammatory effects more selectively by initiating ERK1/2 and c-FOS phosphorylation. Our data also support a role for the TLR4-interacting membrane proteins SCIMP and the SYK kinase axis in mediating TLR4 Y672 phosphorylation to permit downstream inflammatory responses in murine macrophages. The corresponding residue in human TLR4 (Y674) is also required for optimal LPS signaling responses. Our study, thus, reveals how a single PTM on one of the most widely studied innate immune receptors orchestrates downstream inflammatory responses.
    MeSH term(s) Humans ; Animals ; Mice ; Phosphorylation ; Cytokines/metabolism ; Lipopolysaccharides/pharmacology ; Toll-Like Receptor 4 ; Tyrosine/metabolism ; Tyrosine/pharmacology ; Macrophages
    Chemical Substances Cytokines ; Lipopolysaccharides ; Toll-Like Receptor 4 ; Tyrosine (42HK56048U) ; TLR4 protein, human
    Language English
    Publishing date 2023-05-01
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 120108-6
    ISSN 1521-4141 ; 0014-2980
    ISSN (online) 1521-4141
    ISSN 0014-2980
    DOI 10.1002/eji.202250056
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  3. Article ; Online: pTRAPs: Transmembrane adaptors in innate immune signaling.

    Curson, James E B / Luo, Lin / Sweet, Matthew J / Stow, Jennifer L

    Journal of leukocyte biology

    2018  

    Abstract: Transmembrane adaptor proteins (TRAPs) are protein scaffolds and signaling regulators with established roles in signal-induced activation of lymphocytes. A subset of the TRAP family, the palmitoylated TRAPs (pTRAPs), are increasingly emerging with ... ...

    Abstract Transmembrane adaptor proteins (TRAPs) are protein scaffolds and signaling regulators with established roles in signal-induced activation of lymphocytes. A subset of the TRAP family, the palmitoylated TRAPs (pTRAPs), are increasingly emerging with additional roles in innate immune cells. Targeted to lipid rafts, tetraspannin-enriched microdomains, and protein microclusters in membranes, pTRAP scaffolds exert spatiotemporal regulation by recruiting signaling kinases, particularly Src and Syk family members, as well as Csk, and other effectors. In this way, pTRAPs modulate signaling and influence resulting cell responses, including the selective output of inflammatory cytokines and other mediators. Here, we review studies revealing that different pTRAPs work together, often with overlapping or redundant roles, for positive and negative regulation of key innate immune pathways, including Fc receptor and pattern recognition receptor signaling. Recent findings show that pTRAPs can bind directly to innate immune receptors, in addition to other transmembrane binding partners. Thus, pTRAPs are important, multifunctional scaffolds in pathways that are fundamental to diverse innate immune responses.
    Language English
    Publishing date 2018-03-30
    Publishing country England
    Document type Journal Article
    ZDB-ID 605722-6
    ISSN 1938-3673 ; 0741-5400
    ISSN (online) 1938-3673
    ISSN 0741-5400
    DOI 10.1002/JLB.2RI1117-474R
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  4. Article ; Online: The transmembrane adapter SCIMP recruits tyrosine kinase Syk to phosphorylate Toll-like receptors to mediate selective inflammatory outputs.

    Liu, Liping / Lucas, Richard M / Nanson, Jeffrey D / Li, Yan / Whitfield, Jason / Curson, James E B / Tuladhar, Neeraj / Alexandrov, Kirill / Mobli, Mehdi / Sweet, Matthew J / Kobe, Bostjan / Stow, Jennifer L / Luo, Lin

    The Journal of biological chemistry

    2022  Volume 298, Issue 5, Page(s) 101857

    Abstract: Innate immune signaling by Toll-like receptors (TLRs) involves receptor phosphorylation, which helps to shape and drive key inflammatory outputs, yet our understanding of the kinases and mechanisms that mediate TLR phosphorylation is incomplete. Spleen ... ...

    Abstract Innate immune signaling by Toll-like receptors (TLRs) involves receptor phosphorylation, which helps to shape and drive key inflammatory outputs, yet our understanding of the kinases and mechanisms that mediate TLR phosphorylation is incomplete. Spleen tyrosine kinase (Syk) is a nonreceptor protein tyrosine kinase, which is known to relay adaptive and innate immune signaling, including from TLRs. However, TLRs do not contain the conserved dual immunoreceptor tyrosine-based activation motifs that typically recruit Syk to many other receptors. One possibility is that the Syk-TLR association is indirect, relying on an intermediary scaffolding protein. We previously identified a role for the palmitoylated transmembrane adapter protein SCIMP in scaffolding the Src tyrosine kinase Lyn, for TLR phosphorylation, but the role of SCIMP in mediating the interaction between Syk and TLRs has not yet been investigated. Here, we show that SCIMP recruits Syk in response to lipopolysaccharide-mediated TLR4 activation. We also show that Syk contributes to the phosphorylation of SCIMP and TLR4 to enhance their binding. Further evidence pinpoints two specific phosphorylation sites in SCIMP critical for its interaction with Syk-SH2 domains in the absence of immunoreceptor tyrosine-based activation motifs. Finally, using inhibitors and primary macrophages from SCIMP
    MeSH term(s) Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Macrophages/enzymology ; Membrane Proteins/metabolism ; Mice ; Mice, Knockout ; Phosphorylation ; Syk Kinase/metabolism ; Toll-Like Receptor 4/metabolism ; Toll-Like Receptors/genetics ; Toll-Like Receptors/metabolism ; Tyrosine/metabolism ; src-Family Kinases/metabolism
    Chemical Substances Adaptor Proteins, Signal Transducing ; Membrane Proteins ; Toll-Like Receptor 4 ; Toll-Like Receptors ; Tyrosine (42HK56048U) ; Syk Kinase (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2)
    Language English
    Publishing date 2022-03-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2022.101857
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  5. Article ; Online: SCIMP is a spatiotemporal transmembrane scaffold for Erk1/2 to direct pro-inflammatory signaling in TLR-activated macrophages.

    Lucas, Richard M / Liu, Liping / Curson, James E B / Koh, Yvette W H / Tuladhar, Neeraj / Condon, Nicholas D / Das Gupta, Kaustav / Burgener, Sabrina S / Schroder, Kate / Ingley, Evan / Sweet, Matthew J / Stow, Jennifer L / Luo, Lin

    Cell reports

    2021  Volume 36, Issue 10, Page(s) 109662

    Abstract: Immune cells are armed with Toll-like receptors (TLRs) for sensing and responding to pathogens and other danger cues. The role of extracellular-signal-regulated kinases 1/2 (Erk1/2) in TLR signaling remains enigmatic, with both pro- and anti-inflammatory ...

    Abstract Immune cells are armed with Toll-like receptors (TLRs) for sensing and responding to pathogens and other danger cues. The role of extracellular-signal-regulated kinases 1/2 (Erk1/2) in TLR signaling remains enigmatic, with both pro- and anti-inflammatory functions described. We reveal here that the immune-specific transmembrane adaptor SCIMP is a direct scaffold for Erk1/2 in TLR pathways, with high-resolution, live-cell imaging revealing that SCIMP guides the spatial and temporal recruitment of Erk2 to membrane ruffles and macropinosomes for pro-inflammatory TLR4 signaling. SCIMP-deficient mice display defects in Erk1/2 recruitment to TLR4, c-Fos activation, and pro-inflammatory cytokine production, with these effects being phenocopied by Erk1/2 signaling inhibition. Our findings thus delineate a selective role for SCIMP as a key scaffold for the membrane recruitment of Erk1/2 kinase to initiate TLR-mediated pro-inflammatory responses in macrophages.
    MeSH term(s) Animals ; Cytokines/metabolism ; MAP Kinase Signaling System/physiology ; Macrophages/metabolism ; Mice, Transgenic ; Mitogen-Activated Protein Kinase 3/metabolism ; Phosphorylation ; Signal Transduction/physiology ; Toll-Like Receptor 4/metabolism ; Toll-Like Receptors/metabolism
    Chemical Substances Cytokines ; Toll-Like Receptor 4 ; Toll-Like Receptors ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24)
    Language English
    Publishing date 2021-12-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2021.109662
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  6. Article ; Online: SCIMP is a universal Toll-like receptor adaptor in macrophages.

    Luo, Lin / Curson, James E B / Liu, Liping / Wall, Adam A / Tuladhar, Neeraj / Lucas, Richard M / Sweet, Matthew J / Stow, Jennifer L

    Journal of leukocyte biology

    2019  Volume 107, Issue 2, Page(s) 251–262

    Abstract: In innate immune cells, pathogens and danger signals activate TLRs, unleashing potent and tailored inflammatory responses. Previously, we reported that an immune-specific transmembrane adaptor, SLP adaptor and CSK interacting membrane protein (SCIMP), ... ...

    Abstract In innate immune cells, pathogens and danger signals activate TLRs, unleashing potent and tailored inflammatory responses. Previously, we reported that an immune-specific transmembrane adaptor, SLP adaptor and CSK interacting membrane protein (SCIMP), interacts with TLR4 via direct binding to its cytoplasmic TIR domain. SCIMP scaffolds a Src family kinase, Lyn, for TLR4 phosphorylation and activation. Consequently, SCIMP is able to direct selective production of the proinflammatory cytokines IL-6 and IL-12p40 downstream of TLR4 in macrophages. Here, we set out to investigate whether SCIMP also acts as an adaptor for other TLR family members. We report here that SCIMP is phosphorylated and activated in response to agonists of multiple TLRs, including TLR2, TLR3, TLR4, and TLR9. SCIMP also interacts with TLRs that are known to signal from both the cell surface and endosomal compartments. In so doing, this transmembrane adaptor presents Lyn, along with other effectors such as Grb2, Csk, and SLP65, to multiple TLRs during cellular activation. CRISPR-mediated knockout or silencing of SCIMP in macrophages alters TLR signaling outputs and the production of IL-6 and IL-12p40 downstream of multiple TLRs, and upon challenge with live bacteria. Furthermore, the selectivity in cytokine responses is preserved downstream of TLR3, with inducible expression of Il-12p40 and IL-6, but not IFNβ, being SCIMP dependent. SCIMP is thus a universal TLR adaptor for scaffolding the Lyn tyrosine kinase and its effectors to enable responses against a wide range of danger signals.
    MeSH term(s) Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Cells, Cultured ; Cytokines/metabolism ; Inflammation Mediators/metabolism ; Macrophages/cytology ; Macrophages/metabolism ; Mice ; Phosphorylation ; Signal Transduction ; Toll-Like Receptors/genetics ; Toll-Like Receptors/metabolism ; src-Family Kinases/genetics ; src-Family Kinases/metabolism
    Chemical Substances Adaptor Proteins, Signal Transducing ; Cytokines ; Inflammation Mediators ; Toll-Like Receptors ; lyn protein-tyrosine kinase (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2)
    Language English
    Publishing date 2019-08-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 605722-6
    ISSN 1938-3673 ; 0741-5400
    ISSN (online) 1938-3673
    ISSN 0741-5400
    DOI 10.1002/JLB.2MA0819-138RR
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  7. Article ; Online: The histone deacetylase Hdac7 supports LPS-inducible glycolysis and Il-1β production in murine macrophages via distinct mechanisms.

    Ramnath, Divya / Das Gupta, Kaustav / Wang, Yizhuo / Abrol, Rishika / Curson, James E B / Lim, Junxian / Reid, Robert C / Mansell, Ashley / Blumenthal, Antje / Karunakaran, Denuja / Fairlie, David P / Sweet, Matthew J

    Journal of leukocyte biology

    2021  Volume 111, Issue 2, Page(s) 327–336

    Abstract: TLRs reprogram macrophage metabolism, enhancing glycolysis and promoting flux through the tricarboxylic acid cycle to enable histone acetylation and inflammatory gene expression. The histone deacetylase (HDAC) family of lysine deacetylases regulates both ...

    Abstract TLRs reprogram macrophage metabolism, enhancing glycolysis and promoting flux through the tricarboxylic acid cycle to enable histone acetylation and inflammatory gene expression. The histone deacetylase (HDAC) family of lysine deacetylases regulates both TLR-inducible glycolysis and inflammatory responses. Here, we show that the TLR4 agonist LPS, as well as agonists of other TLRs, rapidly increase enzymatic activity of the class IIa HDAC family (HDAC4, 5, 7, 9) in both primary human and murine macrophages. This response was abrogated in murine macrophages deficient in histone deacetylase 7 (Hdac7), highlighting a selective role for this specific lysine deacetylase during immediate macrophage activation. With the exception of the TLR3 agonist polyI:C, TLR-inducible activation of Hdac7 enzymatic activity required the MyD88 adaptor protein. The rapid glycolysis response, as assessed by extracellular acidification rate, was attenuated in Hdac7-deficient mouse macrophages responding to submaximal LPS concentrations. Surprisingly however, reconstitution of these cells with either wild-type or an enzyme-dead mutant of Hdac7 enhanced LPS-inducible glycolysis, whereas only the former promoted production of the inflammatory mediators Il-1β and Ccl2. Thus, Hdac7 enzymatic activity is required for TLR-inducible production of specific inflammatory mediators, whereas it acts in an enzyme-independent fashion to reprogram metabolism in macrophages responding to submaximal LPS concentrations. Hdac7 is thus a bifurcation point for regulated metabolism and inflammatory responses in macrophages. Taken together with existing literature, our findings support a model in which submaximal and maximal activation of macrophages via TLR4 instruct glycolysis through distinct mechanisms, leading to divergent biological responses.
    MeSH term(s) Acetylation ; Animals ; Glycolysis ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism ; Histone Deacetylases/physiology ; Histones ; Humans ; Inflammation/immunology ; Inflammation/pathology ; Interleukin-1beta/genetics ; Interleukin-1beta/metabolism ; Lipopolysaccharides/pharmacology ; Macrophage Activation ; Macrophages/drug effects ; Macrophages/immunology ; Macrophages/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout
    Chemical Substances Histones ; IL1B protein, human ; Interleukin-1beta ; Lipopolysaccharides ; HDAC7 protein, human (EC 3.5.1.98) ; Hdac7 protein, mouse (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98)
    Language English
    Publishing date 2021-11-23
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 605722-6
    ISSN 1938-3673 ; 0741-5400
    ISSN (online) 1938-3673
    ISSN 0741-5400
    DOI 10.1002/JLB.2MR1021-260R
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  8. Article ; Online: Frontline Science: LPS-inducible SLC30A1 drives human macrophage-mediated zinc toxicity against intracellular Escherichia coli.

    Stocks, Claudia J / von Pein, Jessica B / Curson, James E B / Rae, James / Phan, Minh-Duy / Foo, Darren / Bokil, Nilesh J / Kambe, Taiho / Peters, Kate M / Parton, Robert G / Schembri, Mark A / Kapetanovic, Ronan / Sweet, Matthew J

    Journal of leukocyte biology

    2020  Volume 109, Issue 2, Page(s) 287–297

    Abstract: TLR-inducible zinc toxicity is an antimicrobial mechanism utilized by macrophages, however knowledge of molecular mechanisms mediating this response is limited. Here, we show that E. coli exposed to zinc stress within primary human macrophages reside in ... ...

    Abstract TLR-inducible zinc toxicity is an antimicrobial mechanism utilized by macrophages, however knowledge of molecular mechanisms mediating this response is limited. Here, we show that E. coli exposed to zinc stress within primary human macrophages reside in membrane-bound vesicular compartments. Since SLC30A zinc exporters can deliver zinc into the lumen of vesicles, we examined LPS-regulated mRNA expression of Slc30a/SLC30A family members in primary mouse and human macrophages. A number of these transporters were dynamically regulated in both cell populations. In human monocyte-derived macrophages, LPS strongly up-regulated SLC30A1 mRNA and protein expression. In contrast, SLC30A1 was not LPS-inducible in macrophage-like PMA-differentiated THP-1 cells. We therefore ectopically expressed SLC30A1 in these cells, finding that this was sufficient to promote zinc-containing vesicle formation. The response was similar to that observed following LPS stimulation. Ectopically expressed SLC30A1 localized to both the plasma membrane and intracellular zinc-containing vesicles within LPS-stimulated THP-1 cells. Inducible overexpression of SLC30A1 in THP-1 cells infected with the Escherichia coli K-12 strain MG1655 augmented the zinc stress response of intracellular bacteria and promoted clearance. Furthermore, in THP-1 cells infected with an MG1655 zinc stress reporter strain, all bacteria contained within SLC30A1-positive compartments were subjected to zinc stress. Thus, SLC30A1 marks zinc-containing compartments associated with TLR-inducible zinc toxicity in human macrophages, and its ectopic over-expression is sufficient to initiate this antimicrobial pathway in these cells. Finally, SLC30A1 silencing did not compromise E. coli clearance by primary human macrophages, suggesting that other zinc exporters may also contribute to the zinc toxicity response.
    MeSH term(s) Animals ; Cation Transport Proteins/immunology ; Escherichia coli/immunology ; Escherichia coli Infections/immunology ; Humans ; Lipopolysaccharides/immunology ; Macrophages/immunology ; Macrophages/microbiology ; Mice ; Zinc/immunology
    Chemical Substances Cation Transport Proteins ; Lipopolysaccharides ; SLC30A1 protein, human ; Slc30a1 protein, mouse ; Zinc (J41CSQ7QDS)
    Language English
    Publishing date 2020-05-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 605722-6
    ISSN 1938-3673 ; 0741-5400
    ISSN (online) 1938-3673
    ISSN 0741-5400
    DOI 10.1002/JLB.2HI0420-160R
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  9. Article ; Online: HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages.

    Das Gupta, Kaustav / Ramnath, Divya / von Pein, Jessica B / Curson, James E B / Wang, Yizhuo / Abrol, Rishika / Kakkanat, Asha / Moradi, Shayli Varasteh / Gunther, Kimberley S / Murthy, Ambika M V / Stocks, Claudia J / Kapetanovic, Ronan / Reid, Robert C / Iyer, Abishek / Ilka, Zoe C / Nauseef, William M / Plan, Manuel / Luo, Lin / Stow, Jennifer L /
    Schroder, Kate / Karunakaran, Denuja / Alexandrov, Kirill / Shakespear, Melanie R / Schembri, Mark A / Fairlie, David P / Sweet, Matthew J

    Proceedings of the National Academy of Sciences of the United States of America

    2023  Volume 120, Issue 4, Page(s) e2212813120

    Abstract: The immune system must be able to respond to a myriad of different threats, each requiring a distinct type of response. Here, we demonstrate that the cytoplasmic lysine deacetylase HDAC7 in macrophages is a metabolic switch that triages danger signals to ...

    Abstract The immune system must be able to respond to a myriad of different threats, each requiring a distinct type of response. Here, we demonstrate that the cytoplasmic lysine deacetylase HDAC7 in macrophages is a metabolic switch that triages danger signals to enable the most appropriate immune response. Lipopolysaccharide (LPS) and soluble signals indicating distal or far-away danger trigger HDAC7-dependent glycolysis and proinflammatory IL-1β production. In contrast, HDAC7 initiates the pentose phosphate pathway (PPP) for NADPH and reactive oxygen species (ROS) production in response to the more proximal threat of nearby bacteria, as exemplified by studies on uropathogenic
    MeSH term(s) Reactive Oxygen Species/metabolism ; NADP/metabolism ; Triage ; Macrophages/metabolism ; Anti-Infective Agents/metabolism ; Pentose Phosphate Pathway/physiology
    Chemical Substances Reactive Oxygen Species ; NADP (53-59-8) ; Anti-Infective Agents
    Language English
    Publishing date 2023-01-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2212813120
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  10. Article ; Online: Class IIa Histone Deacetylases Drive Toll-like Receptor-Inducible Glycolysis and Macrophage Inflammatory Responses via Pyruvate Kinase M2.

    Das Gupta, Kaustav / Shakespear, Melanie R / Curson, James E B / Murthy, Ambika M V / Iyer, Abishek / Hodson, Mark P / Ramnath, Divya / Tillu, Vikas A / von Pein, Jessica B / Reid, Robert C / Tunny, Kathryn / Hohenhaus, Daniel M / Moradi, Shayli Varasteh / Kelly, Gregory M / Kobayashi, Takumi / Gunter, Jennifer H / Stevenson, Alexander J / Xu, Weijun / Luo, Lin /
    Jones, Alun / Johnston, Wayne A / Blumenthal, Antje / Alexandrov, Kirill / Collins, Brett M / Stow, Jennifer L / Fairlie, David P / Sweet, Matthew J

    Cell reports

    2020  Volume 30, Issue 8, Page(s) 2712–2728.e8

    Abstract: Histone deacetylases (HDACs) drive innate immune cell-mediated inflammation. Here we identify class IIa HDACs as key molecular links between Toll-like receptor (TLR)-inducible aerobic glycolysis and macrophage inflammatory responses. A proteomic screen ... ...

    Abstract Histone deacetylases (HDACs) drive innate immune cell-mediated inflammation. Here we identify class IIa HDACs as key molecular links between Toll-like receptor (TLR)-inducible aerobic glycolysis and macrophage inflammatory responses. A proteomic screen identified the glycolytic enzyme pyruvate kinase M isoform 2 (Pkm2) as a partner of proinflammatory Hdac7 in murine macrophages. Myeloid-specific Hdac7 overexpression in transgenic mice amplifies lipopolysaccharide (LPS)-inducible lactate and promotes a glycolysis-associated inflammatory signature. Conversely, pharmacological or genetic targeting of Hdac7 and other class IIa HDACs attenuates LPS-inducible glycolysis and accompanying inflammatory responses in macrophages. We show that an Hdac7-Pkm2 complex acts as an immunometabolism signaling hub, whereby Pkm2 deacetylation at lysine 433 licenses its proinflammatory functions. Disrupting this complex suppresses inflammatory responses in vitro and in vivo. Class IIa HDACs are thus pivotal intermediates connecting TLR-inducible glycolysis to inflammation via Pkm2.
    MeSH term(s) Acetylation/drug effects ; Animals ; Glycolysis/drug effects ; HEK293 Cells ; Histone Deacetylases/metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Inflammation/pathology ; Lipopolysaccharides/pharmacology ; Macrophages/drug effects ; Macrophages/enzymology ; Macrophages/pathology ; Mice ; Mice, Inbred C57BL ; Protein Binding/drug effects ; Pyruvate Kinase/metabolism ; RAW 264.7 Cells ; Toll-Like Receptors/metabolism
    Chemical Substances Hif1a protein, mouse ; Hypoxia-Inducible Factor 1, alpha Subunit ; Lipopolysaccharides ; Toll-Like Receptors ; Pyruvate Kinase (EC 2.7.1.40) ; Histone Deacetylases (EC 3.5.1.98)
    Language English
    Publishing date 2020-02-25
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2020.02.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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