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  1. Article ; Online: Control of innate immunity by the cGAS-STING pathway.

    Mosallanejad, Kenta / Kagan, Jonathan C

    Immunology and cell biology

    2022  Volume 100, Issue 6, Page(s) 409–423

    Abstract: Within the cytoplasm of mammalian cells is a protein called cyclic GMP-AMP synthase (cGAS), which acts to defend against infection and other threats to the host. cGAS operates in this manner through its ability to detect a molecular occurrence that ... ...

    Abstract Within the cytoplasm of mammalian cells is a protein called cyclic GMP-AMP synthase (cGAS), which acts to defend against infection and other threats to the host. cGAS operates in this manner through its ability to detect a molecular occurrence that should not exist in healthy cells - the existence of DNA in the cytosol. Upon DNA binding, cGAS synthesizes cyclic GMP-AMP (cGAMP), a cyclic dinucleotide that activates the endoplasmic reticulum-localized protein stimulator of interferon genes (STING). STING-mediated signaling culminates in host defensive responses typified by inflammatory cytokine and interferon expression, and the induction of autophagy. Studies over the past several years have established a consensus in the field of the enzymatic activities of cGAS in vitro, as it relates to DNA-induced production of cGAMP. However, much additional work is needed to understand the regulation of cGAS functions within cells, where multiple sources of DNA can create a problem of self and non-self discrimination. In this review, we provide an overview of how the cGAS-STING pathway mediates innate immune responses during infection and other cellular stresses. We then highlight recent progress in the understanding of the increasingly diverse ways in which this DNA-sensing machinery is regulated inside cells, including how cGAS remains inactive to host-derived DNA under conditions of homeostasis.
    MeSH term(s) Animals ; DNA ; Immunity, Innate ; Interferons ; Mammals ; Membrane Proteins/metabolism ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/metabolism
    Chemical Substances Membrane Proteins ; DNA (9007-49-2) ; Interferons (9008-11-1) ; Nucleotidyltransferases (EC 2.7.7.-)
    Language English
    Publishing date 2022-05-25
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 284057-1
    ISSN 1440-1711 ; 0818-9641
    ISSN (online) 1440-1711
    ISSN 0818-9641
    DOI 10.1111/imcb.12555
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Species-specific self-DNA detection mechanisms by mammalian cyclic GMP-AMP synthases.

    Mosallanejad, Kenta / Kennedy, Stephanie N / Bahleda, Kristin M / Slavik, Kailey M / Zhou, Wen / Govande, Apurva A / Hancks, Dustin C / Kranzusch, Philip J / Kagan, Jonathan C

    Science immunology

    2023  Volume 8, Issue 79, Page(s) eabp9765

    Abstract: The mechanisms by which innate immune receptors mediate self-nonself discrimination are unclear. In this study, we found species-specific molecular determinants of self-DNA reactivity by cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) ... ...

    Abstract The mechanisms by which innate immune receptors mediate self-nonself discrimination are unclear. In this study, we found species-specific molecular determinants of self-DNA reactivity by cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase (cGAS). Human cGAS contained a catalytic domain that was intrinsically self-DNA reactive and stimulated interferon responses in diverse cell types. This reactivity was prevented by an upstream amino (N)-terminal domain. The cGAS proteins from several nonhuman primate species exhibited a similar pattern of self-DNA reactivity in cells, but chimpanzee cGAS was inactive even when its amino-terminal domain was deleted. In contrast, the N terminus of mouse cGAS promoted self-DNA reactivity. When expressed within tumors, only self-DNA-reactive cGAS proteins protected mice from tumor-induced lethality. In vitro studies of DNA- or chromatin-induced cGAS activation did not reveal species-specific activities that correlate with self-DNA reactivity observed in macrophages. Cell biological analysis revealed that self-DNA reactivity by human cGAS, but not mouse cGAS, correlated with localization to mitochondria. We found that epitope tag positions affected self-DNA reactivity in cells and that DNA present in cell lysates undermines the reliability of cGAS biochemical fractionations. These studies reveal species-specific diversity of cGAS functions, even within the primate lineage, and highlight experimental considerations for the study of this innate immune receptor.
    MeSH term(s) Animals ; Mice ; Humans ; Reproducibility of Results ; Nucleotides, Cyclic ; DNA/chemistry ; DNA/metabolism ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/chemistry ; Nucleotidyltransferases/metabolism ; Mammals/metabolism
    Chemical Substances cyclic guanosine monophosphate-adenosine monophosphate ; Nucleotides, Cyclic ; DNA (9007-49-2) ; Nucleotidyltransferases (EC 2.7.7.-)
    Language English
    Publishing date 2023-01-20
    Publishing country United States
    Document type Journal Article
    ISSN 2470-9468
    ISSN (online) 2470-9468
    DOI 10.1126/sciimmunol.abp9765
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Candida albicans extracellular vesicles trigger type I IFN signalling via cGAS and STING.

    Brown Harding, Hannah / Kwaku, Geneva N / Reardon, Christopher M / Khan, Nida S / Zamith-Miranda, Daniel / Zarnowski, Robert / Tam, Jenny M / Bohaen, Collins K / Richey, Lauren / Mosallanejad, Kenta / Crossen, Arianne J / Reedy, Jennifer L / Ward, Rebecca A / Vargas-Blanco, Diego A / Basham, Kyle J / Bhattacharyya, Roby P / Nett, Jeniel E / Mansour, Michael K / van de Veerdonk, Frank L /
    Kumar, Vinod / Kagan, Jonathan C / Andes, David R / Nosanchuk, Joshua D / Vyas, Jatin M

    Nature microbiology

    2024  Volume 9, Issue 1, Page(s) 95–107

    Abstract: The host type I interferon (IFN) pathway is a major signature of inflammation induced by the human fungal pathogen, Candida albicans. However, the molecular mechanism for activating this pathway in the host defence against C. albicans remains unknown. ... ...

    Abstract The host type I interferon (IFN) pathway is a major signature of inflammation induced by the human fungal pathogen, Candida albicans. However, the molecular mechanism for activating this pathway in the host defence against C. albicans remains unknown. Here we reveal that mice lacking cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway components had improved survival following an intravenous challenge by C. albicans. Biofilm-associated C. albicans DNA packaged in extracellular vesicles triggers the cGAS-STING pathway as determined by induction of interferon-stimulated genes, IFNβ production, and phosphorylation of IFN regulatory factor 3 and TANK-binding kinase 1. Extracellular vesicle-induced activation of type I IFNs was independent of the Dectin-1/Card9 pathway and did not require toll-like receptor 9. Single nucleotide polymorphisms in cGAS and STING potently altered inflammatory cytokine production in human monocytes challenged by C. albicans. These studies provide insights into the early innate immune response induced by a clinically significant fungal pathogen.
    MeSH term(s) Animals ; Mice ; Candida albicans/pathogenicity ; CARD Signaling Adaptor Proteins/metabolism ; Immunity, Innate ; Interferon Type I/metabolism ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/metabolism ; Signal Transduction ; Candidiasis/metabolism ; Candidiasis/pathology
    Chemical Substances CARD Signaling Adaptor Proteins ; Card9 protein, mouse ; Interferon Type I ; Nucleotidyltransferases (EC 2.7.7.-) ; cGAS protein, mouse (EC 2.7.7.-) ; Sting1 protein, mouse
    Language English
    Publishing date 2024-01-02
    Publishing country England
    Document type Journal Article
    ISSN 2058-5276
    ISSN (online) 2058-5276
    DOI 10.1038/s41564-023-01546-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: IL11-mediated stromal cell activation may not be the master regulator of pro-fibrotic signaling downstream of TGFβ.

    Tan, Yunhao / Mosallanejad, Kenta / Zhang, Qingxiu / O'Brien, Stephen / Clements, Meghan / Perper, Stuart / Wilson, Sarah / Chaulagain, Sudiksha / Wang, Jing / Abdalla, Mary / Al-Saidi, Helen / Butt, Danyal / Clabbers, Anca / Ofori, Kwasi / Dillon, Beth / Harvey, Bohdan / Memmott, John / Negron, Christopher / Winarta, David /
    Tan, Catherine / Biswas, Amlan / Dong, Feng / Morales-Tirado, Vanessa / Lu, Xiaoqing / Singh, Gurminder / White, Michael / Ashley, Shanna / Knight, Heather / Westmoreland, Susan / Phillips, Lucy / Carr, Tracy / Reinke-Breen, Lauren / Singh, Rajeeva / Xu, Jianwen / Wu, Kan / Rinaldi, Lisa / Stoll, Brian / He, Yupeng David / Hazelwood, Lisa / Karman, Jozsef / McCluskey, Andrew / Stine, William / Correia, Ivan / Gauld, Stephen / Levesque, Marc C / Veldman, Geertruida / Hubeau, Cedric / Radstake, Timothy / Sadhukhan, Ramkrishna / Fiebiger, Edda

    Frontiers in immunology

    2024  Volume 15, Page(s) 1293883

    Abstract: Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity and mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell ... ...

    Abstract Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity and mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell activation has been identified as a central mechanism for promoting fibrosis downstream of TGFβ. IL11 signaling has recently been reported to promote fibroblast-to-myofibroblast transition, thus leading to various pro-fibrotic phenotypic changes. We confirmed increased mRNA expression of IL11 and IL11Rα in fibrotic diseases by OMICs approaches and
    MeSH term(s) Humans ; Transforming Growth Factor beta/metabolism ; Interleukin-11 ; Signal Transduction ; Fibrosis ; Myofibroblasts/metabolism
    Chemical Substances Transforming Growth Factor beta ; Interleukin-11
    Language English
    Publishing date 2024-02-22
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2024.1293883
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: The DEAH-box RNA helicase DHX15 activates NF-κB and MAPK signaling downstream of MAVS during antiviral responses.

    Mosallanejad, Kenta / Sekine, Yusuke / Ishikura-Kinoshita, Seiko / Kumagai, Kazuo / Nagano, Tetsuo / Matsuzawa, Atsushi / Takeda, Kohsuke / Naguro, Isao / Ichijo, Hidenori

    Science signaling

    2014  Volume 7, Issue 323, Page(s) ra40

    Abstract: During infection with an RNA virus, the DExD/H-box RNA helicases RIG-I (retinoic acid-inducible gene I) and MDA5 (melanoma differentiation-associated gene 5) activate the interferon regulatory factor 3 (IRF3), nuclear factor κB (NF-κB), c-Jun amino- ... ...

    Abstract During infection with an RNA virus, the DExD/H-box RNA helicases RIG-I (retinoic acid-inducible gene I) and MDA5 (melanoma differentiation-associated gene 5) activate the interferon regulatory factor 3 (IRF3), nuclear factor κB (NF-κB), c-Jun amino-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) signaling pathways through an unknown mechanism involving the adaptor protein MAVS (mitochondrial antiviral signaling). We used a Drosophila misexpression screen to identify DEAH-box polypeptide 15 (DHX15) as an activator of the p38 MAPK pathway. Human DHX15 contributed to the activation of the NF-κB, JNK, and p38 MAPK pathways, but not the IRF3 pathway, in response to the synthetic double-stranded RNA analog poly(I:C) (polyinosinic-polycytidylic acid), and DHX15 was required for optimal cytokine production in response to poly(I:C) and infection with RNA virus. DHX15 physically interacted with MAVS and mediated the MAVS-dependent activation of the NF-κB and MAPK pathways. Furthermore, DHX15 was required for poly(I:C)- and RNA virus-dependent, MAVS-mediated apoptosis. Thus, our findings indicate that, in RIG-I-like receptor signaling, DHX15 specifically stimulates the NF-κB and MAPK pathways downstream of MAVS and contributes to MAVS-mediated cytokine production and apoptosis.
    MeSH term(s) Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Apoptosis/genetics ; Blotting, Western ; Cell Line ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/cytology ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Encephalomyocarditis virus/physiology ; HEK293 Cells ; HeLa Cells ; Host-Pathogen Interactions ; Humans ; Interferon-beta/genetics ; Interferon-beta/metabolism ; Interleukin-6/genetics ; Interleukin-6/metabolism ; JNK Mitogen-Activated Protein Kinases ; MAP Kinase Signaling System ; Mutation ; NF-kappa B/metabolism ; Poly I-C/genetics ; RNA Helicases/genetics ; RNA Helicases/metabolism ; RNA Interference ; Reverse Transcriptase Polymerase Chain Reaction ; Sendai virus/physiology ; TNF Receptor-Associated Factor 6/genetics ; TNF Receptor-Associated Factor 6/metabolism ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/metabolism
    Chemical Substances Adaptor Proteins, Signal Transducing ; Drosophila Proteins ; Interleukin-6 ; MAVS protein, human ; NF-kappa B ; TNF Receptor-Associated Factor 6 ; Tumor Necrosis Factor-alpha ; Interferon-beta (77238-31-4) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; DHX15 protein, human (EC 2.7.7.-) ; RNA Helicases (EC 3.6.4.13) ; Poly I-C (O84C90HH2L)
    Language English
    Publishing date 2014-04-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2417226-1
    ISSN 1937-9145 ; 1945-0877
    ISSN (online) 1937-9145
    ISSN 1945-0877
    DOI 10.1126/scisignal.2004841
    Database MEDical Literature Analysis and Retrieval System OnLINE

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