biostudies-literaturede Oliveira Mann CCEugene V. WeissmanSearle Scholars ProgramHoward Hughes Medical InstituteNCRR NIH HHSNIAID NIH HHSNIHPew Biomedical Scholars ProgramCancer Research InstituteSloan Research FellowshipV FoundationNIDDK NIH HHSBurroughs Wellcome FundCharles H. Hood FoundationDFCI-Novartis Drug Discovery ProgramClaudia Adams Barr Program for Innovative Cancer ResearchNIH-ORIP HEINIGMS NIH HHSNIGMS1165-1175.e5https://www.ebi.ac.uk/biostudies/studies/S-EPMC7733315biostudies-literatureUnknown27(4)Stimulator of interferon genes (STING) is a key regulator of type I interferon and pro-inflammatory responses during infection, cellular stress, and cancer. Here, we reveal a mechanism for how STING balances activation of IRF3- and NF-κB-dependent transcription and discover that acquisition of discrete signaling modules in the vertebrate STING C-terminal tail (CTT) shapes downstream immunity. As a defining example, we identify a motif appended to the CTT of zebrafish STING that inverts the typical vertebrate signaling response and results in dramatic NF-κB activation and weak IRF3-interferon signaling. We determine a co-crystal structure that explains how this CTT sequence recruits TRAF6 as a new binding partner and demonstrate that the minimal motif is sufficient to reprogram human STING and immune activation in macrophage cells. Together, our results define the STING CTT as a linear signaling hub that can acquire modular motifs to readily adapt downstream immunity.Cell reportsModular Architecture of the STING C-Terminal Tail Allows Interferon and NF-κB Signaling Adaptation.PMC7733315AI093589K99AI30258T32 AI007512R01 AI116550U19 AI133524K99 AI130258AI133524T32AI007512P30 DK034854P30DK34854S10 RR029205P41 GM103403R01 AI093589AI116550Orzalli MHLee ASYde Oliveira Mann CCKing DSKranzusch PJKagan JCfalseModular Architecture of the STING C-Terminal Tail Allows Interferon and NF-κB Signaling Adaptation.Stimulator of interferon genes (STING) is a key regulator of type I interferon and pro-inflammatory responses during infection, cellular stress, and cancer. Here, we reveal a mechanism for how STING balances activation of IRF3- and NF-κB-dependent transcription and discover that acquisition of discrete signaling modules in the vertebrate STING C-terminal tail (CTT) shapes downstream immunity. As a defining example, we identify a motif appended to the CTT of zebrafish STING that inverts the typical vertebrate signaling response and results in dramatic NF-κB activation and weak IRF3-interferon signaling. We determine a co-crystal structure that explains how this CTT sequence recruits TRAF6 as a new binding partner and demonstrate that the minimal motif is sufficient to reprogram human STING and immune activation in macrophage cells. Together, our results define the STING CTT as a linear signaling hub that can acquire modular motifs to readily adapt downstream immunity.2019-01-01T00:00:00Z2019 Apr2024-10-19T12:54:43.764Z2021-02-20T14:29:07ZS-EPMC77333153101813110.1016/j.celrep.2019.03.098