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  1. Article ; Online: Sensing Cytosolic DNA Lowers Blood Pressure by Direct cGAMP-Dependent PKGI Activation.

    Su, Jie / Coleman, Pierre / Ntorla, Angeliki / Anderson, Rhys / Shattock, Michael J / Burgoyne, Joseph R

    Circulation

    2023  Volume 148, Issue 13, Page(s) 1023–1034

    Abstract: Background: The major cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) has emerged as a key mediator of inflammation that underlies cardiovascular disease. On interaction with double-stranded DNA, cGAS generates the second messenger 2',3'-cyclic GMP- ... ...

    Abstract Background: The major cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) has emerged as a key mediator of inflammation that underlies cardiovascular disease. On interaction with double-stranded DNA, cGAS generates the second messenger 2',3'-cyclic GMP-AMP (cGAMP) that directly binds to and activates the stimulator of interferon genes, which in turn leads to enhanced expression of genes encoding interferons and proinflammatory cytokines. Here, we show that cGAMP generated by cGAS also directly activates PKGI (cGMP-dependent protein kinase 1), a mechanism that underlies crosstalk between inflammation and blood pressure regulation.
    Methods: The ability of cGAS and cGAMP to activate PKGI was assessed using molecular, cellular, and biochemical analyses, and in myography experiments, as well. The release of cGAMP from the endothelium was measured using an ELISA, and its uptake into the vascular smooth muscle was assessed using molecular and biochemical approaches, including the identification and targeting of specific cGAMP transporters. The blood pressure of wild-type and cGAS
    Results: The detection of cytosolic DNA by cGAS within the vascular endothelium leads to formation of cGAMP that was found to be actively extruded by MRP1 (multidrug resistance protein 1). Once exported, this cGAMP is then imported into neighboring vascular smooth muscle cells through the volume-regulated anion channel, where it can directly activate PKGI. The activation of PKGI by cGAMP mediates vasorelaxation that is dependent on the activity of MRP1 and volume-regulated anion channel, but independent of the canonical nitric oxide pathway. This mechanism of PKGI activation mediates lowering of blood pressure and contributes to hypotension and tissue hypoperfusion during sepsis.
    Conclusions: The activation of PKGI by cGAMP enables the coupling of blood pressure to cytosolic DNA sensing by cGAS, which plays a key role during sepsis by mediating hypotension and tissue hypoperfusion.
    MeSH term(s) Animals ; Mice ; Blood Pressure ; DNA/metabolism ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/metabolism ; Inflammation ; Hypotension
    Chemical Substances cyclic guanosine monophosphate-adenosine monophosphate ; DNA (9007-49-2) ; Nucleotidyltransferases (EC 2.7.7.-)
    Language English
    Publishing date 2023-08-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80099-5
    ISSN 1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
    ISSN (online) 1524-4539
    ISSN 0009-7322 ; 0069-4193 ; 0065-8499
    DOI 10.1161/CIRCULATIONAHA.123.065547
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: LARP4A recognizes polyA RNA via a novel binding mechanism mediated by disordered regions and involving the PAM2w motif, revealing interplay between PABP, LARP4A and mRNA.

    Cruz-Gallardo, Isabel / Martino, Luigi / Kelly, Geoff / Atkinson, R Andrew / Trotta, Roberta / De Tito, Stefano / Coleman, Pierre / Ahdash, Zainab / Gu, Yifei / Bui, Tam T T / Conte, Maria R

    Nucleic acids research

    2019  Volume 47, Issue 8, Page(s) 4272–4291

    Abstract: LARP4A belongs to the ancient RNA-binding protein superfamily of La-related proteins (LARPs). In humans, it acts mainly by stabilizing mRNAs, enhancing translation and controlling polyA lengths of heterologous mRNAs. These activities are known to ... ...

    Abstract LARP4A belongs to the ancient RNA-binding protein superfamily of La-related proteins (LARPs). In humans, it acts mainly by stabilizing mRNAs, enhancing translation and controlling polyA lengths of heterologous mRNAs. These activities are known to implicate its association with mRNA, protein partners and translating ribosomes, albeit molecular details are missing. Here, we characterize the direct interaction between LARP4A, oligoA RNA and the MLLE domain of the PolyA-binding protein (PABP). Our study shows that LARP4A-oligoA association entails novel RNA recognition features involving the N-terminal region of the protein that exists in a semi-disordered state and lacks any recognizable RNA-binding motif. Against expectations, we show that the La module, the conserved RNA-binding unit across LARPs, is not the principal determinant for oligoA interaction, only contributing to binding to a limited degree. Furthermore, the variant PABP-interacting motif 2 (PAM2w) featured in the N-terminal region of LARP4A was found to be important for both RNA and PABP recognition, revealing a new role for this protein-protein binding motif. Our analysis demonstrates the mutual exclusive nature of the PAM2w-mediated interactions, thereby unveiling a tantalizing interplay between LARP4A, polyA and PABP.
    MeSH term(s) Amino Acid Motifs ; Autoantigens/chemistry ; Autoantigens/genetics ; Autoantigens/metabolism ; Binding Sites ; Cloning, Molecular ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Gene Expression ; Genetic Vectors/chemistry ; Genetic Vectors/metabolism ; Humans ; Kinetics ; Models, Molecular ; Poly A/chemistry ; Poly A/genetics ; Poly A/metabolism ; Poly(A)-Binding Proteins/chemistry ; Poly(A)-Binding Proteins/genetics ; Poly(A)-Binding Proteins/metabolism ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; RNA, Messenger/chemistry ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA-Binding Proteins/chemistry ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Ribonucleoproteins/chemistry ; Ribonucleoproteins/genetics ; Ribonucleoproteins/metabolism ; Substrate Specificity ; Thermodynamics ; SS-B Antigen
    Chemical Substances Autoantigens ; Poly(A)-Binding Proteins ; RNA, Messenger ; RNA-Binding Proteins ; Recombinant Proteins ; Ribonucleoproteins ; Poly A (24937-83-5)
    Language English
    Publishing date 2019-02-25
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkz144
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1067: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
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