IRF3 (Interferon regulatory factor 3, Q14653) — curation notes

Provenance note

just deep-research human IRF3 --provider perplexity failed (perplexity provider not
configured in this environment; only falcon and openscientist available). A
falcon run was attempted. These notes are compiled manually from the cached UniProt
record (IRF3-uniprot.txt) and cached publications under publications/, with inline
provenance. No -deep-research-<provider>.md file was fabricated.

Summary of function

IRF3 is a constitutively expressed transcription factor of the interferon regulatory
factor (IRF) family and the master activator of the type I interferon (IFN-alpha/beta)
response to viral infection. It is the terminal, signal-integrating transcription factor
of the cytosolic nucleic-acid–sensing pathways (RIG-I/MDA5-MAVS for RNA; cGAS-STING for
DNA) and the TLR3/TLR4-TRIF pathway.

• Constitutively expressed, single-copy gene; ISRE-binding; activates ISG15 promoter
  PMID:8524823.
• In resting cells IRF3 is a cytoplasmic, autoinhibited monomer. Upon infection the
  adaptors MAVS/STING/TRIF are phosphorylated on a conserved pLxIS motif by TBK1/IKBKE,
  which recruits IRF3 to the adaptor, licensing IRF3 phosphorylation by TBK1
  PMID:25636800.
• The recruitment/activation mechanism is shared across STING, MAVS and TRIF via the
  pLxIS motif; the same motif drives IRF3 dimerization and CBP binding
  PMID:27302953.
• Phospho-IRF3 dimerizes, translocates to the nucleus, binds ISRE/PRD elements and
  recruits CBP/p300 to form the DRAF1/enhanceosome complex driving IFN-beta and ISG
  transcription. Four IRF3 molecules bind the PRDIII-I element of the IFN-beta enhancer
  PMID:17560375.
• Ser-386 pyrophosphorylation by UAP1 (following TBK1 phosphorylation) promotes robust
  type I IFN responses; Uap1-deficient mice are susceptible to lethal viral infection
  PMID:36603579.

Activation cascade / regulation

• Reviews frame IRF3 (with IRF7) as the major modulator of IFN gene expression, activated
  by TBK1/IKKε phosphorylation [PMID:16846591 "Two members of the interferon regulatory
  factor (IRF) family - IRF-3 and IRF-7 - are the major modulators of IFN gene
  expression. Activation of IRF-3 and IRF-7 by TBK1/IKKvarepsilon mediated
  phosphorylation promotes IFN gene expression"; PMID:16979567 "a family of transcription
  factors, interferon regulatory factors (IRFs), plays central roles" in type I IFN
  induction].
• Heavily regulated post-translationally: phosphorylation (TBK1/IKBKE at Ser-385/386/396),
  pyrophosphorylation (UAP1), ISGylation (HERC5, activating), ubiquitination (RBCK1,
  TRIM21, UBE3C — degradative), deubiquitination (USP5), acetylation (KAT8, inhibitory),
  deamidation (CTPS1, inhibitory), and caspase-3 cleavage (inactivating during apoptosis)
  [IRF3-uniprot.txt PTM section].

Negative regulators acting on DNA-binding / coactivator recruitment

• LYAR binds phospho-IRF3 and impedes its DNA-binding capacity, suppressing IFN-beta/ISG
  transcription PMID:31413131.
• ILRUN/C6orf106 interacts with IRF3 and blocks its recruitment to type I IFN promoters
  and reduces nuclear p300/CBP PMID:29802199.

Apoptosis (secondary, non-transcriptional role)

• On mitochondria IRF3 can act in a transcription-independent apoptotic pathway: recruited
  by TOMM70:HSP90AA1 and forming a TOMM70:HSP90AA1:IRF3:BAX complex to induce apoptosis
  [IRF3-uniprot.txt FUNCTION: "is recruited by TOMM70:HSP90AA1 to mitochondrion and forms
  an apoptosis complex TOMM70:HSP90AA1:IRF3:BAX inducing apoptosis (PubMed:25609812)"].
• The active form of IRF-3 induces cell death in macrophages PMID:16846591.
• PBLD study links IRF3 to virus-triggered mitochondrial apoptosis (K313/315-dependent,
  separable from transcriptional S385/386 function) PMID:39362857.
• Caspase-3 cleaves IRF3 (with cGAS, MAVS) to limit cytokine overproduction; this is
  regulation OF IRF3, i.e. IRF3 as substrate, not IRF3 executing apoptosis
  PMID:30878284.

Disease

• Autosomal dominant/recessive functional IRF3 deficiency causes herpes simplex
  encephalitis (IIAE7, MIM:616532); the p.R285Q (GLN-285) variant is characterized
  [IRF3-uniprot.txt DISEASE + PubMed:26216125, PubMed:40973797]. Rare IRF3 variants are
  also associated with life-threatening COVID-19 [PubMed:32972995].

Molecular architecture (for MF review)

• N-terminal DNA-binding domain (residues ~1-113), an IRF tryptophan pentad-repeat that
  recognizes the GAAA-containing ISRE/IRF consensus (5'-AANNGAAA-3' half-sites)
  [IRF3-uniprot.txt DNA_BIND 5..111].
• C-terminal IRF-association domain (IAD) / regulatory domain (~175-427) mediating
  autoinhibition, phospho-triggered dimerization and CBP/p300 binding
  [IRF3-uniprot.txt; PMID:27302953].
• Original report noted IRF3 lacks an intrinsic Gal4-fusion transactivation domain, i.e.
  it activates transcription through coactivator (CBP/p300) recruitment rather than an
  autonomous AD PMID:8524823. Functionally it nonetheless acts
  as a sequence-specific DNA-binding transcriptional activator of ISRE-containing genes.

Curation reasoning notes

• Core MF: sequence-specific dsDNA binding at RNA Pol II cis-regulatory (ISRE) regions +
  DNA-binding transcription activator activity (Pol II specific). Phospho-induced
  homodimerization is a genuine, structurally documented MF.
• Core BP: positive regulation of type I IFN production (and IFN-alpha/beta specifically),
  antiviral innate immune response, cytosolic PRR signaling (RIG-I/MAVS, cGAS/STING),
  TRIF-dependent TLR signaling.
• Core CC: nucleus (active site of transcription), cytoplasm/cytosol (resting, activation).
• GO:0005515 protein binding: uninformative; per CLAUDE.md/skill policy, REMOVE the bare
  generic ones (removal does not deny the interaction). Where a paper supports a specific
  informative MF (e.g. CBP binding → not a distinct MF term needed here; homodimerization
  is already captured by GO:0042803), handle via the specific term rather than inventing one.
• GO:0000122 negative regulation of transcription by RNA pol II (IEA from GO:0001227
  repressor mapping): IRF3 is fundamentally an activator; the repressor mapping is a
  weakly supported ortholog/Ensembl inference. Mark down.
• Apoptosis process terms: real but secondary/non-core (KEEP_AS_NON_CORE).
• IBA annotations (DNA-binding TF activity, Pol II cis-reg binding, nucleus, immune system
  process, regulation of transcription by Pol II) sit at the right level for the IRF family
  and include Q14653 in their own WITH/FROM (expected experimental grounding) — ACCEPT.

2026-10-25 ORGANELLES batch 3 (mitochondrion rows)

• Rows: GO:0005739 EXP (PMID:39362857), IDA (PMID:25609812), IEA (GO_REF:0000044, SL-0173); all located_in, all stay KEEP_AS_NON_CORE. Reasons extended with the check; quotes added to EXP and IEA rows.
• IEA: SL-0173 rests on [file:human/IRF3/IRF3-uniprot.txt "Mitochondrion {ECO:0000269|PubMed:25609812, ECO:0000269|PubMed:39362857}."]; mapping sound.
• PMID:25609812 (full text): PMID:25609812; subcellular fractionation shows virus-induced relocalization that needs Tom70, not Tom20.
• PMID:39362857 (full text): mitochondrial/cytosolic fractions with PMID:39362857; no ER marker, organelle level only.
• No transit peptide or TM. Recruited surface pool (TRAF3/BRAF precedent): binding the OMM receptor Tom70 is one line, no OMM fraction or protease assay. Stays at the root; no GO:0005741.