STING protein (Stimulator of Interferon Genes, encoded by [STING1/TMEM173](/genes/sting1)) is a 42 kDa transmembrane adaptor protein that resides on the endoplasmic reticulum and functions as the central signaling hub of the [cGAS](/genes/cgas)-STING innate immune pathway. Upon binding the cyclic dinucleotide 2'3'-cGAMP produced by cGAS in response to cytosolic DNA, STING undergoes conformational activation, traffics to the Golgi, and triggers [TBK1](/genes/tbk1)-dependent type I interferon and [NF-κB](/entities/nf-kb)-dependent inflammatory cytokine production. Chronic STING activation in brain [microglia](/cell-types/microglia) and [astrocytes](/cell-types/astrocytes) is a major contributor to neuroinflammation in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and aging.
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STING Protein
Overview
STING protein (Stimulator of Interferon Genes, encoded by [STING1/TMEM173](/genes/sting1)) is a 42 kDa transmembrane adaptor protein that resides on the endoplasmic reticulum and functions as the central signaling hub of the [cGAS](/genes/cgas)-STING innate immune pathway. Upon binding the cyclic dinucleotide 2'3'-cGAMP produced by cGAS in response to cytosolic DNA, STING undergoes conformational activation, traffics to the Golgi, and triggers [TBK1](/genes/tbk1)-dependent type I interferon and [NF-κB](/entities/nf-kb)-dependent inflammatory cytokine production. Chronic STING activation in brain [microglia](/cell-types/microglia) and [astrocytes](/cell-types/astrocytes) is a major contributor to neuroinflammation in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and aging.
STING is a homodimeric integral membrane protein with four transmembrane helices per monomer:
Transmembrane region (residues 1-154): Four TM helices anchor STING in the ER membrane and form the dimerization interface
Connector helix (residues 155-180): Links the TM domain to the cytoplasmic domain
Ligand-binding domain (LBD) (residues 181-340): V-shaped dimer that binds cGAMP in the central pocket
C-terminal tail (CTT) (residues 341-379): Contains the TBK1-binding motif (pLxIS) and the [IRF3](/genes/irf3) recruitment site
Conformational Activation
In the resting state, the STING LBD dimer adopts an "open" conformation. cGAMP binding induces a dramatic 180° rotation of the LBD, creating a "closed" conformation that:
Buries cGAMP in a deep pocket at the dimer interface
Reorients the CTT to expose the TBK1-binding pLxIS motif
Promotes STING oligomerization into higher-order complexes required for signaling
Post-Translational Modifications
Palmitoylation (Cys88, Cys91): Required for STING clustering in Golgi and signaling; targeted by inhibitors H-151 and C-178
Phosphorylation (Ser366): By TBK1, creates the IRF3 docking site
K63-linked ubiquitination: By TRIM56 and TRIM32, promotes STING activation
K48-linked ubiquitination: By RNF5 and TRIM30α, targets STING for proteasomal degradation (negative regulation)
Normal Function
Innate Immune Sensing
STING serves as the essential adaptor linking cytosolic DNA detection to interferon and inflammatory responses:
cGAMP binding activates STING, which then traffics from ER → ERGIC → Golgi
At the Golgi, STING recruits TBK1, which phosphorylates both STING (Ser366) and IRF3
Activated IRF3 dimerizes and enters the nucleus to induce IFN-β and interferon-stimulated genes (ISGs)
STING also activates NF-κB through mechanisms involving [IKK](/proteins/ikk-protein) and TRAF6
Autophagy Induction
STING independently activates [autophagy](/entities/autophagy) through a non-canonical pathway:
STING-induced ERGIC membranes serve as platforms for [LC3](/genes/map1lc3b) lipidation
This STING-autophagy axis helps degrade invading pathogens and cytosolic DNA
Impaired STING-autophagy may contribute to cytosolic DNA accumulation in aging
STING in the Brain
[Microglia](/cell-types/microglia-neuroinflammation) are the primary STING-expressing cells in the CNS
Astrocytic STING contributes to reactive astrogliosis and A1 polarization
Neuronal STING expression is low but upregulated by DNA damage stress
STING signaling at the [blood-brain barrier](/mechanisms/blood-brain-barrier) regulates immune cell infiltration
Role in Disease
Alzheimer's Disease
[Tau](/proteins/tau) pathology disrupts the nuclear envelope, releasing chromatin fragments that activate neuronal cGAS-STING
[PQBP1](/genes/pqbp1) acts as a co-sensor that enhances cGAS recognition of [tau](/proteins/tau)-induced cytosolic DNA
STING-driven IFN-β production in microglia promotes complement-mediated synapse elimination
STING knockout rescues cognitive deficits and reduces neuroinflammation in PS19 tauopathy mice
[Amyloid-beta](/proteins/amyloid-beta)-induced mitochondrial damage releases mtDNA, activating cGAS-STING in microglia
[Decout A et al., The cGAS-STING pathway as a therapeutic target in inflammatory diseases (2021) (2021)](https://doi.org/10.1038/s41577-021-00524-z)
[Sliter DA et al., Parkin and PINK1 mitigate STING-induced inflammation (2018) (2018)](https://doi.org/10.1038/s41586-018-0448-9)
[Gulen MF et al., cGAS-STING drives ageing-related inflammation and neurodegeneration (2023) (2023)](https://doi.org/10.1038/s41586-023-06373-1)
[Jin M et al., Tau activates microglia via the PQBP1-cGAS-STING pathway (2021) (2021)](https://doi.org/10.1038/s41593-021-00911-y)
[Unknown, Ablasser A & Chen ZJ, cGAS in action: expanding roles in immunity and inflammation (2019) (2019)](https://doi.org/10.1126/science.aat8657)
[Shang G et al., Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP (2019) (2019)](https://doi.org/10.1038/s41586-019-0998-5)
[McCauley ME et al., C9orf72 in myeloid cells suppresses STING-induced inflammation (2020) (2020)](https://doi.org/10.1038/s41586-020-2625-x)