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-B-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-B 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. SOURCE: Amy,Si-Ying,Lee Brandeis University

Pluto Bioinformatics

GSE128363: Modular architecture of the STING C-terminal tail allows interferon and NF-B signaling adaptation