Modular 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 discr...
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Veröffentlicht in: | Cell reports (Cambridge) 2019-04, Vol.27 (4), p.1165-1175.e5 |
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Sprache: | eng |
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Zusammenfassung: | 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.
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•STING-dependent activation of IRF3 and NF-κB signaling varies between species•A motif in zebrafish STING CTT causes dramatic enhancement of NF-κB signaling•STING CTT-TRAF6 structure explains the mechanism of NF-κB enhancement•Zebrafish CTT module is sufficient to reprogram STING signaling in mammalian cells
de Oliveira Mann et al. define a mechanism that allows emergence of a signaling response in an innate immune pathway. Modular motifs in the STING CTT control the strength and specificity of downstream responses, and evolutionary acquisition of new signaling elements is facilitated by the linear arrangement of the CTT. |
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ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2019.03.098 |