PUBLICATION
Modular Architecture of the STING C-Terminal Tail Allows Interferon and NF-κB Signaling Adaptation
- Authors
- de Oliveira Mann, C.C., Orzalli, M.H., King, D.S., Kagan, J.C., Lee, A.S.Y., Kranzusch, P.J.
- ID
- ZDB-PUB-190425-20
- Date
- 2019
- Source
- Cell Reports 27: 1165-1175.e5 (Journal)
- Registered Authors
- Keywords
- IRF3, NF-κB, STING, TRAF6, cGAS, innate immunity
- MeSH Terms
-
- Zebrafish
- Species Specificity
- TNF Receptor-Associated Factor 6/genetics
- TNF Receptor-Associated Factor 6/metabolism*
- Interferon Type I/metabolism*
- Protein Conformation
- Cells, Cultured
- NF-kappa B/genetics
- NF-kappa B/metabolism*
- Mice
- Humans
- Animals
- Immunity, Innate/immunology*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- HEK293 Cells
- Mice, Knockout
- Macrophages/immunology*
- Macrophages/metabolism
- Membrane Proteins/chemistry
- Membrane Proteins/genetics
- Membrane Proteins/metabolism*
- Membrane Proteins/physiology
- Interferon Regulatory Factor-3/genetics
- Interferon Regulatory Factor-3/metabolism*
- PubMed
- 31018131 Full text @ Cell Rep.
Citation
de Oliveira Mann, C.C., Orzalli, M.H., King, D.S., Kagan, J.C., Lee, A.S.Y., Kranzusch, P.J. (2019) Modular Architecture of the STING C-Terminal Tail Allows Interferon and NF-κB Signaling Adaptation. Cell Reports. 27:1165-1175.e5.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping