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  1. Article: Bacterial cGAS-like enzymes produce 2',3'-cGAMP to activate an ion channel that restricts phage replication.

    Tak, Uday / Walth, Peace / Whiteley, Aaron T

    bioRxiv : the preprint server for biology

    2023  

    Abstract: The mammalian innate immune system uses cyclic GMP-AMP synthase (cGAS) to synthesize the cyclic dinucleotide 2',3'-cGAMP during antiviral and antitumor immune responses. 2',3'-cGAMP is a nucleotide second messenger that initiates inflammatory signaling ... ...

    Abstract The mammalian innate immune system uses cyclic GMP-AMP synthase (cGAS) to synthesize the cyclic dinucleotide 2',3'-cGAMP during antiviral and antitumor immune responses. 2',3'-cGAMP is a nucleotide second messenger that initiates inflammatory signaling by binding to and activating the stimulator of interferon genes (STING) receptor. Bacteria also encode cGAS/DncV-like nucleotidyltransferases (CD-NTases) that produce nucleotide second messengers to initiate antiviral (antiphage) signaling. Bacterial CD-NTases produce a wide range of cyclic oligonucleotides but have not been documented to produce 2',3'-cGAMP. Here we discovered bacterial CD-NTases that produce 2',3'-cGAMP to restrict phage replication. Bacterial 2',3'-cGAMP binds to CD-NTase associated protein 14 (Cap14), a transmembrane protein of unknown function. Using electrophysiology, we show that Cap14 is a chloride-selective ion channel that is activated by 2',3'-cGAMP binding. Cap14 adopts a modular architecture, with an N-terminal transmembrane domain and a C-terminal nucleotide-binding SAVED domain. Domain-swapping experiments demonstrated the Cap14 transmembrane region could be substituted with a nuclease, thereby generating a biosensor that is selective for 2',3'-cGAMP. This study reveals that 2',3'-cGAMP signaling extends beyond metazoa to bacteria. Further, our findings suggest that transmembrane proteins of unknown function in bacterial immune pathways may broadly function as nucleotide-gated ion channels.
    Language English
    Publishing date 2023-07-24
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.07.24.550367
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis.

    Tak, Uday / Dokland, Terje / Niederweis, Michael

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 394

    Abstract: Mycobacterium tuberculosis secretes the tuberculosis necrotizing toxin (TNT) to kill host cells. Here, we show that the WXG100 proteins EsxE and EsxF are essential for TNT secretion. EsxE and EsxF form a water-soluble heterodimer (EsxEF) that assembles ... ...

    Abstract Mycobacterium tuberculosis secretes the tuberculosis necrotizing toxin (TNT) to kill host cells. Here, we show that the WXG100 proteins EsxE and EsxF are essential for TNT secretion. EsxE and EsxF form a water-soluble heterodimer (EsxEF) that assembles into oligomers and long filaments, binds to membranes, and forms stable membrane-spanning channels. Electron microscopy of EsxEF reveals mainly pentameric structures with a central pore. Mutations of both WXG motifs and of a GXW motif do not affect dimerization, but abolish pore formation, membrane deformation and TNT secretion. The WXG/GXW mutants are locked in conformations with altered thermostability and solvent exposure, indicating that the WXG/GXW motifs are molecular switches controlling membrane interaction and pore formation. EsxF is accessible on the bacterial cell surface, suggesting that EsxEF form an outer membrane channel for toxin export. Thus, our study reveals a protein secretion mechanism in bacteria that relies on pore formation by small WXG proteins.
    MeSH term(s) Amino Acid Motifs/genetics ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Bacterial Toxins/metabolism ; Bacterial Toxins/toxicity ; Cell Membrane/metabolism ; Cell Membrane/ultrastructure ; Humans ; Lipid Bilayers/metabolism ; Microscopy, Electron ; Mutation ; Mycobacterium tuberculosis/metabolism ; Mycobacterium tuberculosis/pathogenicity ; Porins/genetics ; Porins/metabolism ; Protein Multimerization ; THP-1 Cells ; Tuberculosis/microbiology ; Tuberculosis/pathology ; Type VII Secretion Systems/genetics ; Type VII Secretion Systems/metabolism
    Chemical Substances Bacterial Proteins ; Bacterial Toxins ; Lipid Bilayers ; Porins ; Type VII Secretion Systems
    Language English
    Publishing date 2021-01-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-20533-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A type VII secretion system in Group B Streptococcus mediates cytotoxicity and virulence.

    Spencer, Brady L / Tak, Uday / Mendonça, Jéssica C / Nagao, Prescilla E / Niederweis, Michael / Doran, Kelly S

    PLoS pathogens

    2021  Volume 17, Issue 12, Page(s) e1010121

    Abstract: Type VII secretion systems (T7SS) have been identified in Actinobacteria and Firmicutes and have been shown to secrete effector proteins with functions in virulence, host toxicity, and/or interbacterial killing in a few genera. Bioinformatic analysis ... ...

    Abstract Type VII secretion systems (T7SS) have been identified in Actinobacteria and Firmicutes and have been shown to secrete effector proteins with functions in virulence, host toxicity, and/or interbacterial killing in a few genera. Bioinformatic analysis indicates that isolates of Group B Streptococcus (GBS) encode at least four distinct subtypes of T7SS machinery, three of which encode adjacent putative T7SS effectors with WXG and LXG motifs. However, the function of T7SS in GBS pathogenesis is unknown. Here we assessed the role of the most abundant GBS T7SS subtype during GBS pathogenesis. In a murine model of hematogenous meningitis, mice infected with GBS lacking a functional T7SS or lacking the secreted WXG100 effector EsxA exhibited less mortality, lower bacterial burdens in tissues, and decreased inflammation in the brain compared to mice infected with the parental GBS strain. We further showed that this T7SS induces cytotoxicity in brain endothelium and that EsxA contributes to these cytotoxicity phenotypes in a WXG motif-dependent manner. Finally, we determined that EsxA is a pore-forming protein, thus demonstrating the first role for a non-mycobacterial EsxA homolog in pore formation. This work reveals the importance of a T7SS in host-GBS interactions and has implications for T7SS effector function in other Gram-positive bacteria.
    MeSH term(s) Animals ; Bacterial Proteins/metabolism ; Cells, Cultured ; Humans ; Mice ; Streptococcal Infections/metabolism ; Streptococcus agalactiae/metabolism ; Streptococcus agalactiae/pathogenicity ; Type VII Secretion Systems/metabolism ; Virulence/physiology
    Chemical Substances Bacterial Proteins ; Type VII Secretion Systems
    Language English
    Publishing date 2021-12-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1010121
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Toxin secretion and trafficking by Mycobacterium tuberculosis.

    Pajuelo, David / Tak, Uday / Zhang, Lei / Danilchanka, Olga / Tischler, Anna D / Niederweis, Michael

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 6592

    Abstract: The tuberculosis necrotizing toxin (TNT) is the major cytotoxicity factor of Mycobacterium tuberculosis (Mtb) in macrophages. TNT is the C-terminal domain of the outer membrane protein CpnT and gains access to the cytosol to kill macrophages infected ... ...

    Abstract The tuberculosis necrotizing toxin (TNT) is the major cytotoxicity factor of Mycobacterium tuberculosis (Mtb) in macrophages. TNT is the C-terminal domain of the outer membrane protein CpnT and gains access to the cytosol to kill macrophages infected with Mtb. However, molecular mechanisms of TNT secretion and trafficking are largely unknown. A comprehensive analysis of the five type VII secretion systems of Mtb revealed that the ESX-4 system is required for export of CpnT and surface accessibility of TNT. Furthermore, the ESX-2 and ESX-4 systems are required for permeabilization of the phagosomal membrane in addition to the ESX-1 system. Thus, these three ESX systems need to act in concert to enable trafficking of TNT into the cytosol of Mtb-infected macrophages. These discoveries establish new molecular roles for the two previously uncharacterized type VII secretion systems ESX-2 and ESX-4 and reveal an intricate link between toxin secretion and phagosomal permeabilization by Mtb.
    MeSH term(s) Antigens, Bacterial/metabolism ; Bacterial Outer Membrane Proteins ; Bacterial Proteins ; Bacterial Toxins/metabolism ; Cell Death ; Macrophages/metabolism ; Mycobacterium tuberculosis/metabolism ; Phagosomes/metabolism ; Toxins, Biological/metabolism ; Type VII Secretion Systems
    Chemical Substances Antigens, Bacterial ; Bacterial Outer Membrane Proteins ; Bacterial Proteins ; Bacterial Toxins ; ESAT-6 protein, Mycobacterium tuberculosis ; Rv3903 protein, Mycobacterium tuberculosis ; Toxins, Biological ; Type VII Secretion Systems
    Language English
    Publishing date 2021-11-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-26925-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: NAD

    Pajuelo, David / Gonzalez-Juarbe, Norberto / Tak, Uday / Sun, Jim / Orihuela, Carlos J / Niederweis, Michael

    Cell reports

    2018  Volume 24, Issue 2, Page(s) 429–440

    Abstract: Mycobacterium tuberculosis (Mtb) kills infected macrophages by inhibiting apoptosis and promoting necrosis. The tuberculosis necrotizing toxin (TNT) is a secreted nicotinamide adenine dinucleotide ( ... ...

    Abstract Mycobacterium tuberculosis (Mtb) kills infected macrophages by inhibiting apoptosis and promoting necrosis. The tuberculosis necrotizing toxin (TNT) is a secreted nicotinamide adenine dinucleotide (NAD
    MeSH term(s) Animals ; Apoptosis/drug effects ; Bacterial Toxins/toxicity ; Biocatalysis/drug effects ; Cytoprotection/drug effects ; Humans ; Jurkat Cells ; Macrophages/drug effects ; Macrophages/microbiology ; Macrophages/pathology ; Mice, Inbred C57BL ; Mitochondria/drug effects ; Mitochondria/pathology ; Models, Biological ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/metabolism ; NAD/deficiency ; NAD/metabolism ; NAD+ Nucleosidase/metabolism ; Necrosis ; Niacinamide/pharmacology ; Protein Kinases/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; THP-1 Cells ; Tumor Necrosis Factor-alpha/metabolism
    Chemical Substances Bacterial Toxins ; Tumor Necrosis Factor-alpha ; NAD (0U46U6E8UK) ; Niacinamide (25X51I8RD4) ; MLKL protein, human (EC 2.7.-) ; Protein Kinases (EC 2.7.-) ; RIPK1 protein, human (EC 2.7.11.1) ; RIPK3 protein, human (EC 2.7.11.1) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; NAD+ Nucleosidase (EC 3.2.2.5)
    Language English
    Publishing date 2018-07-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2018.06.042
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: The tuberculosis necrotizing toxin is an NAD

    Tak, Uday / Vlach, Jiri / Garza-Garcia, Acely / William, Doreen / Danilchanka, Olga / de Carvalho, Luiz Pedro Sório / Saad, Jamil S / Niederweis, Michael

    The Journal of biological chemistry

    2018  Volume 294, Issue 9, Page(s) 3024–3036

    Abstract: Upon host infection, ...

    Abstract Upon host infection,
    MeSH term(s) Amino Acid Sequence ; Bacterial Toxins/chemistry ; Bacterial Toxins/metabolism ; Hydrolysis ; Intracellular Space/microbiology ; Models, Molecular ; Mycobacterium tuberculosis/metabolism ; Mycobacterium tuberculosis/physiology ; NAD/metabolism ; NAD+ Nucleosidase/metabolism ; NADP/metabolism ; Protein Conformation ; Protein Domains
    Chemical Substances Bacterial Toxins ; NAD (0U46U6E8UK) ; NADP (53-59-8) ; NAD+ Nucleosidase (EC 3.2.2.5)
    Language English
    Publishing date 2018-12-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.RA118.005832
    Database MEDical Literature Analysis and Retrieval System OnLINE

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