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Modular architecture of the STING C-terminal tail allows interferon and NF-κB signaling adaptation

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE128363 | GEO | 2019/06/10

REPOSITORIES: GEO

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