Journal Article

DZNE-2024-00017

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Cutting Edge: STING Induces ACLY Activation and Metabolic Adaptations in Human Macrophages through TBK1.

Nickenig, M. ; Mangan, M. S. J. ; Lee, H. E. ; Symeonidis, K. ; Henne, A. ; Kaiser, R.Extern* ; Geißmar, E. ; Garritsen, H. ; Abdullah, Z. ; Hiller, K. ; Latz, E.DZNE* ; Lauterbach, M. A.

2024
Soc. Bethesda, Md.

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Please use a persistent id in citations: doi:10.4049/jimmunol.2200835

Abstract: 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.

Keyword(s): Humans (MeSH) ; ATP Citrate (pro-S)-Lyase: metabolism (MeSH) ; DNA (MeSH) ; Interferon Regulatory Factor-3: metabolism (MeSH) ; Macrophages: metabolism (MeSH) ; Membrane Proteins: metabolism (MeSH) ; NF-kappa B: metabolism (MeSH) ; Nucleotidyltransferases: metabolism (MeSH) ; Protein Serine-Threonine Kinases: metabolism (MeSH) ; ATP Citrate (pro-S)-Lyase ; DNA ; Interferon Regulatory Factor-3 ; Membrane Proteins ; NF-kappa B ; Nucleotidyltransferases ; Protein Serine-Threonine Kinases ; TBK1 protein, human ; STING1 protein, human

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Contributing Institute(s):

1. Innate Immunity in Neurodegeneration (AG Latz ; AG Latz)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; SCOPUS ; Web of Science Core Collection

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