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Cell Rep April 23, 2019; 27 (4): 1165-1175.e5.
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Modular Architecture of the STING C-Terminal Tail Allows Interferon and NF-κB Signaling Adaptation.

de Oliveira Mann CC , Orzalli MH , King DS , Kagan JC , Lee ASY , Kranzusch PJ .

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.

PubMed ID: 31018131
PMC ID: PMC7733315
Article link: Cell Rep

Species referenced: Xenopus
Genes referenced: elavl2 irf3 nos2 sting1 tbk1 traf6
GO keywords: inflammatory response [+]

Article Images: [+] show captions