IRF3 (Interferon Regulatory Factor 3)

IRF3 is the constitutively expressed, cytoplasmic transcription factor that executes the type I interferon (IFN-I) arm of innate immune signaling. Inactive as a cytoplasmic monomer, IRF3 is phosphorylated by tbk1 (and IKKε) on a C-terminal serine/threonine cluster, homodimerizes, translocates to the nucleus, and binds IFN-regulatory element (IRF-E / ISRE) motifs in target gene promoters — driving transcription of IFN-β (IFNB1) and hundreds of interferon-stimulated genes (ISGs). It is the terminal transcriptional effector of the cgas-sting pathway (as well as the RIG-I/MDA5–MAVS and TLR3/TRIF axes), downstream of sting and tbk1, and is functionally distinct from the parallel nf-kb arm of cGAS-STING that drives pro-inflammatory cytokine production. In aging, chronic low-level IRF3 activation by self-derived cytosolic DNA — leaked mitochondrial DNA, senescent-cell cytosolic chromatin fragments — contributes to the type I IFN inflammatory signature observed in aged tissues and amplifies the SASP of senescent cells.

Identity

UniProt: Q14653 (IRF3_HUMAN) — Swiss-Prot manually curated; reviewed entry
NCBI Gene: 3661
HGNC: 6118; official gene symbol IRF3
Ensembl: ENSG00000126456
OMIM: 603734
Gene locus: 19q13.33 (chromosome 19)
Protein length: 427 amino acids (canonical isoform, UniProt Q14653 confirmed)
GenAge: not listed — IRF3 is not a curated GenAge/HAGR aging gene; aging relevance is mechanistic (inflammaging effector) rather than direct longevity-gene evidence needs-canonical-id (GenAge entry absent; tag for future periodic re-check)
Mouse ortholog: Irf3 (Mus musculus); phosphorylation sites Ser388/Ser390 correspond to human Ser385/Ser386; functional conservation well established

Protein structure

IRF3 contains three canonical structural regions and a C-terminal regulatory domain characteristic of the IRF family:

Domain	Residues (approx.)	Function
DNA-binding domain (DBD)	5–111	IRF tryptophan pentad repeat (W-x-x-x-x-W motif); sequence-specific binding to ISRE elements
Disordered linker	91–136	Flexible; connects DBD to IAD
Nuclear export signal (NES)	139–149	Constitutive cytoplasmic retention in resting cells
IRF-association domain (IAD)	~190–390	Mediates latent autoinhibition and, upon activation, homodimerization; also contains HERC5 interaction region (200–360)
C-terminal regulatory domain	~380–427	Serine/threonine cluster; primary phosphorylation target of TBK1/IKKε; conformational switch

The DNA-binding domain uses a helix-turn-helix motif with a conserved tryptophan repeat (five W residues, ~11 residues apart) that contacts the major groove of ISRE DNA sequences. The IAD mediates both the autoinhibitory intramolecular interaction in resting IRF3 and the activating homodimerization interface after phosphorylation — a single conformational switch controlled by the C-terminal phosphorylation state. Lin 1999 localized the transactivation domain to aa 134–394, with the N-terminal boundary between aa 134 and 151 and the C-terminal boundary between aa 357 and 394; two autoinhibitory domains are located at C-terminal aa 380–427 and the internal region aa 98–240 ¹.

Post-translational modifications

The following PTMs are annotated in UniProt Q14653 (accessed 2026-05-13):

Key activating phosphorylation sites (C-terminal regulatory domain):

Site	Modification	Notes
Ser-385	Phosphorylation	Regulatory site; Lin 1999 showed S385/S386 substitution with Asp does not activate transcription — these residues regulate the adjacent Ser-Thr cluster (aa 396–405) rather than serving as direct TBK1 substrates; later structural work positions Ser-386 as key conformational switch
Ser-386	Pyrophosphorylation (and mono-phosphorylation)	Key conformational switch; TBK1-dependent phosphorylation confirmed (UniProt: “by TBK1”); pyrophosphorylation also reported; S385/S386 regulatory role described in Lin 1999
Ser-396	Phosphorylation	TBK1 and IKKε substrate (UniProt: “by IKKE and TBK1”); part of the inducible phosphoacceptor cluster (aa 396–405) identified as primary activation locus in Lin 1999; required for full IRF3 transactivation activity
Ser-398	Phosphorylation	Part of the serine cluster (aa 396–405); contributes to conformational change
Thr-404	Phosphorylation	Cluster residue
Ser-427	Phosphorylation	Cluster residue (UniProt-annotated; also denoted Ser-405 in some mouse-aligned numbering — use human Q14653 numbering throughout)

Other phosphorylation sites annotated by UniProt: Thr-3, Ser-14, Thr-75, Ser-97, Ser-123, Ser-175 (microbial infection context — by viral kinase, pathogen evasion), Thr-180, Ser-188, Thr-237, Thr-244, Thr-253.

Non-phosphorylation PTMs:

Lys-366: acetylation (turnover regulation)
Lys-193, Lys-360, Lys-366: ubiquitination (proteasomal degradation)
Multiple sites: ISGylation (antiviral IFN feedback loop)
Asn-85: deamidation (viral evasion mechanism — HCMV UL37x1 targets this site)

Mouse vs human numbering note. The human sites (Ser-385/Ser-386) correspond to mouse Irf3 Ser-388/Ser-390. This two-residue offset is a common source of confusion in the literature; whenever cross-species claims are made, verify the species-specific numbering. Note that Lin 1999 uses human IRF3 numbering throughout (427 aa canonical isoform) ¹.

Function: type I IFN transcriptional effector

IRF3 is constitutively expressed in most cell types and maintained at low basal activity by intramolecular autoinhibition — the IAD is held in a closed conformation that occludes the dimerization interface and the DNA-binding surface ¹.

Activation cascade:

Upstream innate sensor (cGAS, RIG-I, TLR3) detects pathogen-associated or damage-associated DNA/RNA
Adaptor protein (STING, MAVS, or TRIF) recruits and activates tbk1 and/or IKKε
TBK1/IKKε phosphorylate the IRF3 C-terminal serine/threonine cluster; the primary inducible phosphoacceptor sites are in the Ser-396/Ser-398/Thr-404 cluster (aa 396–405 per Lin 1999); Ser-386 serves as a key conformational switch; Ser-385/Ser-386 play regulatory roles modulating the cluster ¹ ² ³
Phosphorylation disrupts autoinhibition → conformational change → IAD exposed → IRF3 homodimerizes
Homodimer translocates to nucleus (overcoming the NES)
Dimer binds ISRE motifs (consensus: GAAA(C/T)NGAAACT) in promoters of IFNB1 and ISGs
Recruits co-activators CBP/p300 (HATs) → chromatin remodeling → transcription

Key transcriptional outputs:

IFN-β (IFNB1): primary IRF3 target; IFN-β is then secreted, binds IFNAR in autocrine/paracrine fashion, and activates the STAT1/STAT2 → IRF9 → ISGF3 complex → drives amplified ISG transcription via the JAK-STAT pathway (jak-stat-pathway)
ISGs: hundreds of interferon-stimulated genes with antiviral effector functions (OAS, IFIT, Mx, ISG15, TRIM proteins)

IRF3 vs IRF7: IRF3 is constitutively expressed and initiates the acute IFN-β response. IRF7, the IRF3 paralog, is itself an ISG — it is induced by the initial IFN-β wave and amplifies IFN-α production in the second wave. In sustained/chronic signaling (as in aging and interferonopathies), IRF7 may carry more of the ISG transcriptional load, but IRF3 remains the initiator ⁴.

Function: signal integration node

IRF3 is the convergence point for four distinct innate immune input pathways, all of which signal through TBK1/IKKε:

Upstream sensor	Ligand	Adaptor → kinase → IRF3
cGAS	Cytosolic dsDNA (microbial, mtDNA, CCFs)	cGAS → 2’3’-cGAMP → sting → TBK1 → IRF3
RIG-I / MDA5	Cytosolic dsRNA / ssRNA	RIG-I/MDA5 → MAVS → TBK1 → IRF3
TLR3	Endosomal dsRNA	TLR3 → TRIF → TBK1 → IRF3
TLR4	LPS (partial)	TLR4 → TRIF → TBK1 → IRF3 (in addition to dominant TRIF → NF-κB route)

All four pathways converge on TBK1 phosphorylation of IRF3 C-terminal cluster (Ser-396, Ser-386, Ser-398, Thr-404) as the activating event ⁴ ⁵.

IRF3 vs NF-κB distinction. The cgas-sting pathway activates two parallel transcriptional arms from the STING scaffold:

IRF3 arm — STING palmitoylation → TBK1 → IRF3 → type I IFN and ISG transcription
NF-κB arm — STING → IKK complex → IκB degradation → nf-kb → pro-inflammatory cytokines (TNF-α, IL-6, IL-1β)

These arms are functionally and temporally separable. Per West 2015, the mtDNA-driven inflammatory response in aged mitochondria signals through the IRF3 arm, not primarily the NF-κB arm ⁶. Subsequent reviews emphasize that in aging contexts, the IRF3-driven type I IFN signature is the dominant chronic output — NF-κB activation by STING is more prominent in acute/high-dose settings ⁴.

Aging relevance

Type I IFN inflammaging signature

Aged tissues — particularly brain, liver, and kidneys — display a chronic, low-level ISG expression signature consistent with constitutive IRF3 activation. This interferon-associated transcriptomic footprint is a component of the broader inflammaging phenotype. Gulen et al. 2023 demonstrated causally — using both genetic Sting−/− mice and pharmacological STING inhibition (H-151) in aged C57BL/6J mice (19–20 months) — that chronic STING activation drives aging-related neuroinflammation and neurodegeneration, including microgliosis, hippocampal neuron loss, and cognitive decline (Morris water maze, fear conditioning) — implicating IRF3 (as STING’s downstream effector via TBK1) in brain aging pathology ⁷. The mechanistic driver in this context is mtDNA released from disrupted mitochondria in aged microglia activating cGAS→STING. Note: Gulen 2023 measured pTBK1 as the STING signaling readout; IRF3 knockout was not directly tested in this study.

Dimension	Status	Notes
Pathway conserved in humans?	yes	TBK1-IRF3 axis is highly conserved; ISRE-binding activity documented in human cells
Phenotype conserved in humans?	partial	Type I IFN gene signature elevated in aged human blood (PBMC); human ISG upregulation in aging is documented but causal attribution to IRF3 specifically is not resolved
Replicated in humans?	no	No in-vivo human genetic experiments; causal role inferred from mouse Sting−/− + in-vitro human cell work

needs-human-replication — Chronic IRF3 activation as a causal driver of human aging phenotypes has not been directly demonstrated.

Senescence-associated secretory phenotype (SASP)

Senescent cells accumulate cytosolic chromatin fragments (CCFs) and cytoplasmic DNA (from nuclear envelope breakdown, micronuclei rupture, and retrotransposon cDNA). CCFs activate cgas, producing cGAMP → sting → tbk1 → IRF3 phosphorylation → IFN-β and ISG induction. This IRF3-driven IFN component is part of the SASP and is distinct from the IL-6/IL-8 component driven by NF-κB ⁸.

Glück et al. 2017 (Nat Cell Biol) showed that cGAS senses cytosolic chromatin fragments (CCFs, arising from lamin B1 degradation) in senescent cells, and that the resulting SASP response requires cGAS-STING signaling ⁸. Cell models used: cGAS-KO MEFs (Mb21d1−/− mice, C57BL/6 background) and WI-38 human fibroblasts. Senescence was induced by multiple triggers including oxidative stress (40% O2), ionizing radiation (12 Gy), HRasV12 oncogene, and palbociclib — confirming generality. The cGAS-STING pathway drives both ISG induction (Cxcl10/Ifi44) and classical SASP cytokines (IL-6, TNF-α); IRF3 is implicated as the STING→TBK1 downstream transcriptional effector for the ISG/IFN component. Yang et al. 2017 (PNAS) demonstrated that cGAS is essential for cellular senescence in MEFs and human BJ cells — cGAS knockout suppressed the senescence program (SA-β-Gal activity) and abrogated SASP gene expression (IL6, IL8, IL1β, MMP12) in response to etoposide, irradiation, and spontaneous immortalization ⁹. Note: Yang 2017 does not contain aged-tissue in-vivo data; Gulen 2023 is the authoritative source for in-vivo aging causation.

mtDNA-driven inflammaging

Mitochondrial DNA (mtDNA) that leaks into the cytosol (during mitochondrial stress, membrane permeabilization, or TFAM deficiency) is a potent cGAS ligand. West et al. 2015 demonstrated that mtDNA stress primes the antiviral innate immune response via the cGAS-STING-TBK1-IRF3 axis, establishing IRF3 as the terminal transcriptional effector of mtDNA-driven IFN production ⁶. Key quantitative evidence: ISG mRNAs in TFAM-depleted cells were reduced 70–90% in the absence of STING, confirming cGAS-STING as the predominant driver; siRNA knockdown of either TBK1 or IRF3 robustly blocked ISG expression; enhanced nuclear accumulation of IRF3 was confirmed by immunofluorescence in TFAM-depleted cells. The model used Tfam+/− MEFs (C57BL/6 background) with ~50% mtDNA depletion. The inflammatory signal here flows through IRF3, not NF-κB — an important distinction from bacterial-LPS-type inflammation which is NF-κB-dominant.

Hematopoietic stem cell (HSC) exhaustion by chronic IFN

Chronic IFN-α exposure activates dormant HSCs and drives them into cycling, exhausting the HSC pool over time ¹⁰. Essers 2009 demonstrated this specifically for IFN-α (delivered i.p. as recombinant mIFNα4): IFNAR-STAT1-Sca-1 signaling drives HSC proliferation, and chronic repetitive IFN-α stimulation leads to marked competitive disadvantage of wild-type HSCs in repopulation assays. IFN-α is primarily produced downstream of IRF7 (an ISG itself, amplified by the autocrine IFN loop that IRF3 initiates); thus IRF3’s contribution to HSC exhaustion is indirect — IRF3 initiates IFN-β, which triggers JAK-STAT-IRF7 → IFN-α amplification. This is one mechanism by which chronic inflammaging contributes to stem-cell-exhaustion. needs-human-replication — causal HSC exhaustion via this axis is established in mice only.

Pathway membership

cgas-sting — load-bearing terminal effector; IRF3 is the key-node at the transcriptional output step
jak-stat-pathway — IFNB1 secreted by IRF3 drives autocrine IFNAR → JAK1/TYK2 → STAT1/STAT2 → ISGF3 feedback loop; IRF3 is upstream trigger, JAK-STAT is the amplification cascade
nf-kb — parallel arm from the same upstream stimuli; important to distinguish from IRF3; they have distinct promoter targets

Key interactors

Interactor	Role	Evidence type
tbk1	Activating kinase (primary); phosphorylates Ser-396 cluster (primary inducible sites aa 396–405) and Ser-386 (UniProt-confirmed); Ser-385/Ser-386 are regulatory modulators of the cluster per Lin 1999	In-vitro kinase assay + genetic KO; West 2015 IRF3 siRNA confirms functional requirement
IKKε (IKBKE)	Activating kinase (parallel/redundant with TBK1); can phosphorylate same sites	Biochemical + KO
sting	Upstream scaffold; recruits TBK1 to the Golgi signalosome where IRF3 docking occurs	Co-IP, structural
MAVS	Upstream scaffold (RIG-I/MDA5 arm); recruits TBK1 → IRF3	Genetic
CBP / p300	Nuclear co-activator; recruited by phospho-IRF3 dimer to IFN-β enhanceosome	Co-IP
IRF7	Paralog; forms IRF3-IRF7 heterodimers in some contexts; IRF7 is the primary IFN-α driver	Biochemical
HERC5	ISGylation E3 ligase; ISGylates IRF3 at multiple sites; affects IRF3 turnover and activity	Biochemical
PP2A	Phosphatase; dephosphorylates IRF3 → resets the cycle	Biochemical
PIN1	Prolyl isomerase; reported to regulate IRF3 turnover (pro-degradation)	Biochemical

Disease associations

Herpes simplex encephalitis (HSE) susceptibility. A Q285 loss-of-function variant in human IRF3 impairs TLR3-dependent IRF3 activation and is associated with herpes simplex virus encephalitis susceptibility (OMIM: IIAE7). Demonstrates the non-redundant role of IRF3 in CNS antiviral defense in humans ¹¹.

Interferonopathies. IRF3 is the terminal effector of multiple interferonopathy circuits (AGS — Aicardi-Goutières syndrome, STING gain-of-function/COPA syndrome, TREX1-deficiency). In these monogenic diseases, chronic IRF3 activation by uncontrolled nucleic acid sensing drives severe systemic type I IFN-driven inflammation. These conditions model — at an accelerated and severe scale — the chronic low-level IRF3 activity proposed to underlie inflammaging.

Lupus / autoimmunity. Elevated type I IFN (largely IRF3-downstream) is the dominant biomarker and pathogenic driver of systemic lupus erythematosus (SLE). Gain-of-function variants in cGAS, STING, and TRex1 converge on IRF3 overactivation.

Druggability and interventions

No FDA-approved direct IRF3 modulator exists. Clinical-stage innate immune drugs act primarily on upstream nodes (cGAS, STING, TBK1).

Aging-context druggability tier: 3 (predicted druggable; no aging-validated probe; no clinical compound targeting IRF3 directly even in oncology or autoimmune indications). Rationale for aging-context tier vs maximum druggability: IRF3 lacks a deep ATP-binding pocket accessible to small molecules, making it inherently harder to drug than kinases upstream. Direct IRF3 modulators remain in early preclinical stages.

Upstream indirect suppressors (all suppress IRF3 phosphorylation by targeting the kinase or scaffold):

TBK1 inhibitors — amlexanox (AMP-activated; approved for canker sores; off-target TBK1 inhibition), MRT67307, BX795, GSK8612 (selective, preclinical) — suppress IRF3 phosphorylation at Ser-385/Ser-396; no aging indication needs-human-replication
cGAS inhibitors — G140 (Lama 2019), G150, TDI-6570 (early-stage discovery compounds) — prevent cGAMP production, blocking cGAS-STING-TBK1-IRF3 axis at the top
STING inhibitors — H-151 (Haag 2018, preclinical mouse), C-178/C-176 (covalent agonists, paradoxically suppressive at high dose — complex pharmacology) — block STING → TBK1 → IRF3 signaling

STING agonists (ADU-S100, MK-1454, DMXAA) activate IRF3 downstream — these are tested in oncology as tumor-immunotherapy adjuvants, the opposite direction from aging-context suppression.

No STING or cGAS inhibitor is currently FDA-approved or in Phase 3 trials for any aging indication. long-term-unknown

Limitations and gaps

needs-human-replication — causal role of IRF3-driven type I IFN in human aging phenotypes (vs correlative ISG signature) is not established; Gulen 2023 mouse Sting−/− data is the current best causal evidence
needs-mechanism-clarity — IRF3 vs IRF7 division of transcriptional labor in aged tissues; in chronic low-level signaling, IRF7 (an ISG itself) may amplify and dominate ISG output while IRF3 initiates; quantitative partition of the IRF3 vs IRF7 contribution to the aged ISG signature is not resolved
needs-gtex-query — GTEx v2 IRF3 age-correlation not pulled; populate per sops/finding-tissue-expression.md on next lint pass
long-term-unknown — IRF3 selective (vs TBK1 or STING) inhibition in aging-relevant in-vivo models has not been tested
needs-replication — IRF3 contribution to SASP (vs NF-κB arm) is based on Glück 2017 and Yang 2017; the relative quantitative contribution has not been formally dissected in aged tissues
needs-canonical-id — GenAge entry absent as of 2026-05-13; schedule periodic re-check during lint passes

Footnotes

doi:10.1128/MCB.19.4.2465 · Lin R et al. · Mol Cell Biol 1999 · in-vitro (293 cells, COS cells; Sendai virus infection; yeast one-hybrid; EMSA; co-IP) · defined IRF3 as 55-kDa constitutively expressed cytoplasmic protein; localized transactivation domain to aa 134–394; defined two autoinhibitory domains (C-terminal aa 380–427; internal aa 98–240); showed Ser/Thr cluster at aa 396–405 constitutes the inducible phosphoacceptor sites; Ser-385/Ser-386 play regulatory roles modulating the adjacent cluster but are not themselves direct activation sites (S385/S386→Asp did not activate transcription); established IRF3 homodimerization upon virus-induced phosphorylation and nuclear translocation with CBP/p300 recruitment · local-pdf: available ↩ ↩² ↩³ ↩⁴
doi:10.1126/science.1081315 · Sharma S et al. · Science 2003 · n=cell lines · in-vitro + genetic · identified IKK-related kinase pathway (TBK1/IKKε) as the kinase responsible for IRF3 phosphorylation and IFN antiviral response; cited_by: 1657 · local-pdf: not_oa ↩
doi:10.1038/ni921 · Fitzgerald KA et al. · Nat Immunol 2003 · in-vitro + genetic · IKKε and TBK1 are essential components of the IRF3 signaling pathway; loss-of-function suppresses virus-induced IFN-β; cited_by: 2659 · local-pdf: not_oa ↩
doi:10.1038/s41580-020-0244-x · Hopfner KP, Hornung V · Nat Rev Mol Cell Biol 2020 · review · comprehensive review of molecular mechanisms and cellular functions of cGAS-STING signaling including TBK1-IRF3 axis and IRF3/IRF7 division of labor; cited_by: 1745 · local-pdf: available ↩ ↩² ↩³
doi:10.1038/s41577-021-00524-z · Decout A et al. · Nat Rev Immunol 2021 · review · cGAS-STING pathway as therapeutic target; covers IRF3 convergence from multiple innate immune sensing arms; cited_by: 1949 · local-pdf: pending ↩
doi:10.1038/nature14156 · West AP et al. · Nature 2015 · in-vitro (Tfam+/− MEFs and TFD inducible-depletion MEFs, C57BL/6 background; cGas−/− MEFs; Sting−/− MEFs; BMDM) + in-vivo (Tfam+/− mice, LCMV infection model) · mtDNA stress (TFAM heterozygous KO causing ~50% mtDNA depletion) primes antiviral innate immune response; of 45 most overexpressed genes, 39 were ISGs; ISG mRNAs reduced 70–90% in absence of STING; knockdown of TBK1 or IRF3 robustly blocked ISG expression; cGAS-STING signals via TBK1-IRF3/7 axis (IRF3 is the terminal transcriptional effector; NF-κB arm is parallel but not the primary ISG driver in this context); cited_by: 1759 · local-pdf: available ↩ ↩²
doi:10.1038/s41586-023-06373-1 · Gulen MF et al. · Nature 2023 · in-vivo (C57BL/6J aged mice 19–20 months; Sting−/− mice; H-151 pharmacological STING inhibitor 750 nmol i.p. 5 days/week; microglia-specific cGasR241E gain-of-function model; snRNA-seq of 9,505 hippocampal cells) + ex-vivo human adipose tissue · aged mice show elevated ISG and proinflammatory gene signature in kidneys and liver; STING inhibition (H-151) reduces inflammatory cytokines (B2m, Il1b, Il6, Tnf, Cxcl10, Isg15, Ifitm3) in aged mice; aged Sting−/− mice independently confirm findings; in brain: microgliosis reduced, NeuN+ neuron density preserved in CA1, synaptophysin intensity increased; cognitive improvement in Morris water maze and fear conditioning (P=3×10−3 for fear conditioning); pTBK1 (Ser172) elevated in aged brains, reduced by H-151; cGAMP elevated in aged vs young brain (ELISA); mechanistic driver is mtDNA released from disrupted mitochondria in aged microglia activating cGAS→STING; IRF3 implicated as downstream STING→TBK1 effector (pTBK1 measured; IRF3 KO not directly tested); cited_by: 751 · local-pdf: available ↩
doi:10.1038/ncb3586 · Glück S et al. · Nat Cell Biol 2017 · in-vitro (cGAS-KO MEFs from Mb21d1−/− mice, C57BL/6 background; WI-38 human fibroblasts) + in-vivo (mouse irradiation + NrasG12V liver model) · cGAS senses cytosolic chromatin fragments (CCFs from lamin B1 degradation) in senescent cells; senescence triggers tested: oxidative stress (40% O2), ionizing radiation (12 Gy), HRasV12 oncogene activation, palbociclib (CDK4 inhibitor); cGAS-STING pathway drives IFN component of SASP (Cxcl10/ISGs) and classical SASP cytokines (IL-6, TNF-α); IRF3 is implicated as downstream STING→TBK1 effector; cited_by: 1053 · local-pdf: available ↩ ↩²
doi:10.1073/pnas.1705499114 · Yang H et al. · PNAS 2017 · in-vitro (cGas−/− MEFs C57BL/6 background; BJ human foreskin fibroblasts-TERT immortalized; cGas−/− BJ cells via TALEN; B16F10 melanoma cells) + in-vivo (cGas−/− mice) · cGAS essential for cellular senescence; cGas−/− MEFs immortalize faster (passages 11–12 vs 15–16 for WT); senescence triggers: spontaneous immortalization (serial passage), etoposide (3 μM and 10 μM MEFs; 10–20 μM BJ), ionizing radiation (3 Gy X-ray); cGAS deletion abrogates SASP gene expression (IL6, IL8, IL1β, MMP12); cGAS-dependent IRF3 activation (described generically via STING→TBK1→IRF3/NF-κB signaling) contributes to senescence program; does NOT contain aged-tissue in-vivo data — discussion notes “it would be very interesting to determine whether cGAS plays a role in normal aging”; Gulen 2023 is authoritative for in-vivo aging causation; cited_by: 940 · local-pdf: available ↩
doi:10.1038/nature07815 · Essers MAG et al. · Nature 2009 · in-vivo (C57BL/6 mice, Ifnar−/− and Stat1−/− mice; chimera experiments) · IFN-α (recombinant mIFNα4, 10,000 units i.p.) activates dormant LSKCD150+ HSCs via IFNAR-STAT1-Sca-1 signaling; acute IFN-α drives HSC cell-cycle entry; chronic IFN-α (repeated poly(I:C) stimulation via Mx1-Cre model) results in complete loss of functional wild-type HSCs in chimera repopulation assays; Sca-1 upregulation is downstream of STAT1 and required for IFN-α-induced HSC proliferation; cited_by: 1333 · local-pdf: available ↩
UniProt Q14653 (IRF3_HUMAN), Swiss-Prot reviewed entry · accessed 2026-05-13 · disease annotation: IIAE7 (HSE susceptibility, Q285 loss-of-function variant); PTM site list; domain annotations ↩

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