期刊
CELL REPORTS
卷 27, 期 4, 页码 1165-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.03.098
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资金
- Claudia Adams Barr Program for Innovative Cancer Research
- Charles H. Hood Foundation
- Cancer Research Institute CLIP grant
- V Foundation V Scholar Award
- DFCI-Novartis Drug Discovery Program
- Searle Scholars Program
- Pew Biomedical Scholars Program
- Sloan Research Fellowship
- NIH [AI133524, AI093589, AI116550, P30DK34854, T32AI007512, K99AI30258]
- Burroughs Wellcome Fund
- NIGMS [P41 GM103403]
- NIH-ORIP HEI grant [S10 RR029205]
- DOE Argonne National Laboratory Advanced Photon Source [DE-AC02-06CH11357]
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-kappa 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-kappa 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.
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