Cutting Edge: STING Induces ACLY Activation and Metabolic Adaptations in Human Macrophages through TBK1.
Maximilian NickenigMatthew S J ManganHye Eun LeeKonstantinos SymeonidisAntonia HenneRomina KaiserEike GeißmarHendrikus GarritsenZeinab AbdullahKarsten HillerEicke LatzMario A LauterbachPublished in: Journal of immunology (Baltimore, Md. : 1950) (2023)
The 2'3'-cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of IFN genes (STING) pathway can sense infection and cellular stress by detecting cytosolic DNA. Upon ligand binding, cGAS produces the cyclic dinucleotide messenger cGAMP, which triggers its receptor STING. Active STING initiates gene transcription through the transcription factors IFN regulatory factor 3 (IRF3) and NF-κB and induces autophagy, but whether STING can cause changes in the metabolism of macrophages is unknown. In this study, we report that STING signaling activates ATP-citrate lyase (ACLY) by phosphorylation in human macrophages. Using genetic and pharmacologic perturbation, we show that STING targets ACLY via its prime downstream signaling effector TANK (TRAF family member-associated NF-κB activator)-binding kinase 1 (TBK1). We further identify that TBK1 alters cellular metabolism upon cGAMP treatment. Our results suggest that STING-mediated metabolic reprogramming adjusts the cellular response to DNA sensing in addition to transcription factor activation and autophagy induction.
Keyphrases
- transcription factor
- signaling pathway
- dendritic cells
- endothelial cells
- oxidative stress
- genome wide
- cell death
- protein kinase
- immune response
- dna binding
- genome wide identification
- nuclear factor
- circulating tumor
- endoplasmic reticulum stress
- lps induced
- gene expression
- cell free
- induced pluripotent stem cells
- cell proliferation
- cystic fibrosis
- binding protein
- nucleic acid
- replacement therapy
- type iii