The IKK complex and TBK1/IKKε are recruited to STING through distinct mechanisms to activate NF-κB signaling

Stimulator of interferon genes (STING) is a highly conserved signaling molecule that coordinates an antiviral innate immune response through activation of the nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3) signaling pathways. In addition to an antiviral response, STING-mediated NF-κB signaling also leads to an inflammatory response, which can cause substantial pathology. However, the molecular mechanism whereby STING drives inflammation is poorly understood, and this has hindered the development of anti-inflammatory strategies targeting this pathway. Here, we define an evolutionarily conserved mechanism whereby STING activates NF-κB signaling via recruitment of inhibitor of NF-κB kinase subunit γ (IKKγ) in an M1-linked ubiquitin-dependent manner. We also show that the more recently evolved carboxyl-terminal tail of STING cooperates with the IKKγ-IKK complex for NF-κB–dependent expression of pro-inflammatory genes in mammalian cells through the kinases TBK1 (TANK-binding kinase 1)/IKKε. Thus, the expression of the key inflammatory genes CCL3 and CCL4 requires the formation of M1-linked ubiquitin and the activation of NF-κB, but we do not detect a role for IRF3 in STING-driven NF-κB signaling.

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Journal
Science Immunology
Published
2026-10-09
DOI
https://doi.org/10.1126/sciimmunol.aeh5148
Primary Topic
interferon and immune responses
Type
article
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article

The IKK complex and TBK1/IKKε are recruited to STING through distinct mechanisms to activate NF-κB signaling

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Science Immunology
interferon and immune responses
article

The IKK complex and TBK1/IKKε are recruited to STING through distinct mechanisms to activate NF-κB signaling

Louise Dalskov, Veit Hornung, Gabrielle Haas, Anna Lorentzen, Katarzyna Kjøge, Rune Hartmann, Jean‐Luc Imler, Aneta Jurkiewicz, Mads Gyrd‐Hansen, Julia M. Kamper, Hans Henrik Gad, Hua Cai, Jan J. Enghild, Kasper Grønbjerg Winther, Weisheng Luo, Anna Hvarregaard Christensen, Andreas Bondrup Bagger, Wenhao He, Yuqiang Chen, Che Stafford, Jiyong Liu, Cathrine Silberbauer Jensen, Katrine Gårn Gulstad
article en

Abstract

Stimulator of interferon genes (STING) is a highly conserved signaling molecule that coordinates an antiviral innate immune response through activation of the nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3) signaling pathways. In addition to an antiviral response, STING-mediated NF-κB signaling also leads to an inflammatory response, which can cause substantial pathology. However, the molecular mechanism whereby STING drives inflammation is poorly understood, and this has hindered the development of anti-inflammatory strategies targeting this pathway. Here, we define an evolutionarily conserved mechanism whereby STING activates NF-κB signaling via recruitment of inhibitor of NF-κB kinase subunit γ (IKKγ) in an M1-linked ubiquitin-dependent manner. We also show that the more recently evolved carboxyl-terminal tail of STING cooperates with the IKKγ-IKK complex for NF-κB–dependent expression of pro-inflammatory genes in mammalian cells through the kinases TBK1 (TANK-binding kinase 1)/IKKε. Thus, the expression of the key inflammatory genes CCL3 and CCL4 requires the formation of M1-linked ubiquitin and the activation of NF-κB, but we do not detect a role for IRF3 in STING-driven NF-κB signaling.

Science ImmunologyVol. 11(124)
Aarhus University (DK), LEO Foundation (DK), State Key Laboratory of Respiratory Disease (CN), Institut de Biologie Moléculaire et Cellulaire (FR), Université de Strasbourg (FR), Ludwig-Maximilians-Universität München (DE), Guangzhou Medical University (CN)
Openalex Percentile: Top 19%
interferon and immune responses
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