XB-ART-56516Cell Rep April 23, 2019; 27 (4): 1165-1175.e5.
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 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
Article link: Cell Rep
Genes referenced: elavl2 irf3 sting1 traf6
GO keywords: inflammatory response
Article Images: [+] show captions
|Figure 1STING C-Terminal Modules Control the Balance of Downstream IRF3 and NF-κB Signaling (A) Reconstitution of the cGAS-STING pathway in human cells using a phylogenetically diverse panel of vertebrate STING alleles. Luciferase reporters were used to monitor cGAS-STING dependent interferon β (IFNβ; blue) and NF-κB (orange) responses. Species shown are as follows: 1, human (Homo sapiens); 2, marmoset (Callithrix jacchus); 3, mouse (Mus musculus); 4, cat (Felis catus); 5, seal (Leptonychotes weddellii); 6, cattle (Bos taurus); 7, boar (Sus scrofa); 8, bat (Rousettus aegyptiacus); 9, manatee (Trichechus manatus latirostris); 10, Tasmanian devil (Sarcophilus harrisii); 11, ostrich (Struthio camelus australis); 12, crested ibis (Nipponia nippon); 13, lizard (Anolis carolinensis); 14, turtle (Chelonia mydas); 15, western clawed frog (Xenopus tropicalis); 16, African clawed frog (Xenopus laevis); 17, coelacanth (Latimeria chalumnae); 18, salmon (Salmo salar); 19, zebrafish (Danio rerio); and 20, ghost shark (Callorhinchus milii). (B) Schematics of STING domain organization (TM, transmembrane domain; CDN, cyclic dinucleotide binding domain; CTT, C-terminal tail). Cellular reporter assay as in (A), mapping the motif responsible for enhanced NF-κB signaling to the CTT of zebrafish STING. (C) Cellular reporter assay and schematics as in (B), comparing downstream signaling outputs of human STING with human STING containing the zebrafish STING CTT sequence. The zebrafish STING CTT is sufficient to enhance NF-κB signaling. Cellular reporter assay data are representative of at least three independent experiments. Data are plotted with error bars representing the SD of the mean.|