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  • iNOS and The β‐Cell: Barre1 Updegraff

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    This document discusses inducible nitric oxide synthase (iNOS) and how it relates to beta cell injury. iNOS expression is induced by proinflammatory cytokines like interleukin-1 beta (IL-1β) and interferon gamma (IFNγ) through signaling pathways involving NF-κB and STAT1 transcription factors. A single nucleotide change in the iNOS promoter (cGAS mutation) increases its sensitivity to IL-1β alone. This mutation partially restores iNOS promoter activity in response to IL-1β when NF-κB sites are mutated. Future research aims to further understand the proteins and transcription factors interacting with the cGAS promoter and other roles of IKK in the IL-1β signaling pathway.

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    This document discusses inducible nitric oxide synthase (iNOS) and how it relates to beta cell injury. iNOS expression is induced by proinflammatory cytokines like interleukin-1 beta (IL-1β) and interferon gamma (IFNγ) through signaling pathways involving NF-κB and STAT1 transcription factors. A single nucleotide change in the iNOS promoter (cGAS mutation) increases its sensitivity to IL-1β alone. This mutation partially restores iNOS promoter activity in response to IL-1β when NF-κB sites are mutated. Future research aims to further understand the proteins and transcription factors interacting with the cGAS promoter and other roles of IKK in the IL-1β signaling pathway.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PDF, TXT or read online from Scribd
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    Download as pdf or txt
    61 views13 pages

    iNOS and The β‐Cell: Barre1 Updegraff

    Uploaded by

    oneantisnoant
    This document discusses inducible nitric oxide synthase (iNOS) and how it relates to beta cell injury. iNOS expression is induced by proinflammatory cytokines like interleukin-1 beta (IL-1β) and interferon gamma (IFNγ) through signaling pathways involving NF-κB and STAT1 transcription factors. A single nucleotide change in the iNOS promoter (cGAS mutation) increases its sensitivity to IL-1β alone. This mutation partially restores iNOS promoter activity in response to IL-1β when NF-κB sites are mutated. Future research aims to further understand the proteins and transcription factors interacting with the cGAS promoter and other roles of IKK in the IL-1β signaling pathway.

    Copyright:

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    of 13

    iNOSandTheCell

    Barre1Updegra

    InducibleNitricOxideSynthase
    Notcons?tu?velyac?ve,butuponinduc?on, increases~100,000fold Arginine+NADPH+O2 iNOS LCitrulline+NO Mul?plesignaltransduc?onpathwayscanact toinduceiNOS: NFB:IL1 Signaling STAT1:IFNSignaling p38MAPK:CellularStress,possibleIFN involvement

    Interferon JAK1/2
    phosph

    Interleukin1 ?
    orylaD on

    Otherproinammatorycytokines

    STAT1
    IncreasedNO ProducDon
    NFB

    WTiNOSPromoter:
    NFB

    GAS

    1Kb

    Progressive InammaDon cellInjury

    STAT1Binding
    IFNbindsatcellsurfacereceptor,inducestyrosine phosphoryla?onofJAK1/2 PhosphorylatedJAK1/2recruitsandphosphorylatestwo STAT1monomers TwoSTAT1homodimerizeandassociatewithIRF9 Ac?vatedhomodimertranslocatestothenucleusand bindstoIFNac?vatedsite(GAS)oftargetgene promoters

    NFB

    GAS

    NFB

    1Kb

    NFBBinding
    IL1bindstoIL1RandMyD88isrecruited,MyD88inturn recruitsIRAK1andIRAK4 IRAK4phosphorylatesitspartnerIRAK1 phosphoIRAK1recruitsTRAF6andE1enzymecomplex forms E1Complexpolyubiqui?natesTRAF6andrecruitsTAK1 Ac?vatedTAK1phosphorylatesIBKinase(IKK) IKKphosphorylatesNFBessen?almodulator(NEMO) NEMO isproteasomallydegradedandNFBdimers translocatetothenucleus FreeNFBdimersbindtoBsitesoftargetgenes
    NFB

    GAS

    NFB

    1Kb

    iNOSandTheCell
    IL1 P P
    STAT1
    IB

    IFN
    P P
    STAT1

    P P
    IB IB

    IK
    RelA p50 RelA p50

    RelA

    p50

    P P

    STAT1

    iNOS
    B

    GAS

    STAT1

    IK

    Crea?ngaconsensusGAS
    Wildtype:
    NFB

    GAS

    NFB

    1Kb

    TTCCCCTAA

    ConsensusGAS:
    NFB

    cGAS

    NFB

    1Kb

    TTCCCCGAA

    AonenucleoDdesubsDtuDonintheiNOSgenepromoter increasessensiDvitytoIL1
    600 500

    RelaDvePromoterAcDvity (PercentIL1 Response)

    IL1 IL1+IFN

    400 300 200 100 0

    iNOSWT

    cGAS

    GASmut

    AonenucleoDdesubsDtuDonintheiNOSgenepromoter increasessensiDvitytoIL1
    2000 1800 1600 1400 1200 1000 800 600 400 200 0 0.1ng/ml IL1 1ng/ml IL1 0.1ng/ml IL1+ 1ng/ml IL1+

    RelaDvePromoterAcDvity (PercentIL1Response)

    WT cGAS

    CanourconsensusmutaDonrestore responsetoIL1ofmutatedNFBsites?
    iNOScGAS/distalBdoublemutant:
    NFB DistalB Mutant

    cGAS

    NFB

    1Kb

    iNOScGAS/proximalBdoublemutant:
    NFB

    cGAS

    NFB ProximalB Mutant

    1Kb

    OurcGASmutaDonparDallyrescuesiNOSpromoter acDvityinresponsetoIL1, IL1+IFN

    DoesourcGASmutaDoninteractwithp65 orp50oftheNFBpathway?
    450 400

    WildtypeiNOSPromoter
    RelaDvePromoterAcDvity (PercentageofIL1Response)

    250 200 150 100 50 0

    cGASiNOSPromoter

    RelaDvePromoterAcDvity (PercentageofIL1Response)

    350 300 250 200 150 100 50 0

    IL1

    IL1 + IFN

    IL1

    IL1 + IFN

    siScr sip65 sip50 sip65+p50

    siScr sip65 sip50 sip65+p50

    FutureResearchAims
    Elucida?ngproteins,accessoryfactors,and transcrip?onfactorbindingtothecGASiNOS promoter DeterminingotherrolesofIKK Cytosolicinterac?onofIL1signal intermediateswithNODreceptors Cellcycleregula?onanddecisionof autophagy,apoptosis,ornecrosis

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