Transcription‐independent Regulation of STING Activation and Innate Immune Responses by IRF8 in Monocytes

Luo, Wei-Wei; Tong, Zhen; Cao, Pan; Wang, Fu-Bing; Liu, Ying; Zheng, Zhou-Qin; Wang, Su-Yun; Li, Shu; Wang, Yan-Yi

doi:10.1038/s41467-022-32401-1

Cited by 54interferon and immune responsesImmune Response and InflammationInflammasome and immune disorders

Transcription‐independent Regulation of STING Activation and Innate Immune Responses by IRF8 in Monocytes

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Luo, Wei-Wei, Tong, Zhen, Cao, Pan, Wang, Fu-Bing, Liu, Ying, Zheng, Zhou-Qin, Wang, Su-Yun, Li, Shu +1 more·2022·Nature Communications

DOI 10.1038/s41467-022-32401-1PMC PMC9381507

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Abstract

Sensing of cytosolic DNA of microbial or cellular/mitochondrial origin by cGAS initiates innate immune responses via the adaptor protein STING. It remains unresolved how the activity of STING is balanced between a productive innate immune response and induction of autoimmunity. Here we show that interferon regulatory factor 8 (IRF8) is essential for efficient activation of STING-mediated innate immune responses in monocytes. This function of IRF8 is independent of its transcriptional role in monocyte differentiation. In uninfected cells, IRF8 remains inactive via sequestration of its IRF-associated domain by its N- and C-terminal tails, which reduces its association with STING. Upon triggering the DNA sensing pathway, IRF8 is phosphorylated at Serine 151 to allow its association with STING via the IRF-associated domain. This is essential for STING polymerization and TBK1-mediated STING and IRF3 phosphorylation. Consistently, IRF8-deficiency impairs host defense against the DNA virus HSV-1, and blocks DNA damage-induced cellular senescence. Bone marrow-derived mononuclear cells which have an autoimmune phenotype due to deficiency of Trex1, respond to IRF-8 deletion with reduced pro-inflammatory cytokine production. Peripheral blood mononuclear cells from systemic lupus erythematosus patients are characterized by elevated phosphorylation of IRF8 at the same Serine residue we find to be important in STING activation, and in these cells STING is hyper-active. Taken together, the transcription-independent function of IRF8 we describe here appears to mediate STING activation and represents an important regulatory step in the cGAS/STING innate immune pathway in monocytes.

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IRF8 is directly activated by PU.1 and contributes to the activation of SALL1, CX3CR1, and STING.
“Moreover, IRF8 is directly activated by PU.1 and contributes to the activation of SALL1, CX3CR1, and STING (also known as TMEM173) [35, 63].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [63]
The Results section ('Irf8 mediates polymerization of Sting and its recruitment of Irf3'; page not available) supports IRF8's role in STING activation after DNA virus infection. Our copy does not say that PU.1 directly activates IRF8 or that IRF8 activates SALL1 or CX3CR1; its reference to an IRF8–PU.1 complex does not establish direct activation. (LLM, conf=0.90)
Experimental — accuracy not yet measured
The current dogma dictates that the host-derived STING pathway is the converging critical responder.
“a finding that is in sharp contrast to the current dogma which dictates that host-derived STING pathway is the converging critical responder.79–81”
From Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy efficacy following cryoablation (2023) · cites this paper as [80]
The Introduction describes STING as critical to innate immune responses and notes that the cGAS–STING pathway is involved in anti-tumor immunity. The Discussion also links STING to cancer prognosis. Neither section establishes the more specific claim that host-derived STING is the converging critical responder. (LLM, conf=0.82)
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Authors: Luo, W.-W., Tong, Z., Cao, P., Wang, F.-B., Liu, Y., Zheng, Z.-Q., Wang, S.-Y., Li, S., & Wang, Y.-Y.
Affiliations: Chinese Academy of Sciences (CN)
Wuhan University (CN)
Corresponding author: Wang, Yan-Yi
ORCID: Luo, Wei-Wei
Cao, Pan
Liu, Ying
Zheng, Zhou-Qin
Li, Shu
Wang, Yan-Yi
Venue: Nature Communications
Publisher: Springer Science and Business Media LLC
Published: 2022-08-16
Volume: 13
Issue: 1
Pages: 4822-4822
ISSN: 2041-1723 (ISSN-L)
DOI: 10.1038/s41467-022-32401-1
PMC: PMC9381507
OpenAlex: W4291993620
Cited by: 53
References: 61
Citations by year: 2026: 12 · 2025: 13 · 2024: 17 · 2023: 10 · 2022: 1
FWCI: 3.92
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Nature Communications (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Natural Science Foundation of China (31870869)
the Key Research Programs of Frontier Sciences funded by Chinese Academy of Sciences (ZDBS-LY-SM033) the Youth Innovation Promotion Association CAS
Topics: Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords: IRF8, STING activation, monocytes, cGAS-STING pathway, cytosolic DNA sensing, TBK1, IRF3 phosphorylation, herpes simplex virus type 1, cellular senescence, autoimmunity, systemic lupus erythematosus, TREX1, inflammatory cytokines
MeSH terms: Interferon Regulatory Factor-8, DNA, Immunity, Innate, Leukocytes, Mononuclear, Membrane Proteins, Monocytes, Nucleotidyltransferases, Serine, Interferon Regulatory Factors, Interferon Regulatory Factor-3

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Transcription‐independent Regulation of STING Activation and Innate Immune Responses by IRF8 in Monocytes

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