Affinage

HCFC2

Host cell factor 2 · UniProt Q9Y5Z7

Length
792 aa
Mass
86.8 kDa
Annotated
2026-06-10
31 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HCFC2 (HCF-2) is a nuclear, kelch-repeat (beta-propeller) protein originally defined as a second member of the host cell factor family that, like HCF-1, associates with the herpes simplex virus transactivator VP16 and supports assembly of the VP16–Oct-1–DNA complex (PMID:10196288, PMID:11711630). Functional comparison establishes a key divergence from HCF-1: HCFC2 stabilizes the VP16-induced complex but cannot mediate transcriptional activation from it, and residue differences between the fifth and sixth kelch repeats of the beta-propeller dictate this selectivity (PMID:10196288, PMID:11711630). Beyond its viral cofactor role, HCFC2 is required for IRF1- and IRF2-dependent transcription, acting at the Tlr3 promoter to promote IRF1 and IRF2 binding and thereby enabling Tlr3 expression and a broad set of IRF2-dependent interferon-regulated genes in macrophages; loss-of-function compromises inflammatory cytokine and type I IFN responses and survival during influenza and herpes simplex virus 1 infection (PMID:28970238). HCFC2 retains an N-terminal SAS1 self-association element yet, unlike HCF-1, is not proteolytically processed (PMID:10958670).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 1999 High

    Established HCFC2 as a distinct HCF family protein and asked whether it shares HCF-1's VP16 cofactor function, showing it associates with VP16 and assembles the Oct-1/DNA complex but less efficiently, with selectivity localized to its beta-propeller kelch repeats.

    Evidence Sequence analysis, in vitro complex assembly, and chimeric protein construction comparing HCF-1 and HCF-2 beta-propeller domains

    PMID:10196288

    Open questions at the time
    • Functional consequence of dynamic subcellular localization not resolved
    • Testis-enriched expression not mechanistically explained
    • No structural model of the HCF-2 beta-propeller
  2. 2000 Medium

    Tested whether the SAS1 self-association element functions only to hold cleaved subunits together, finding HCFC2 retains a functional SAS1 element despite not being proteolyzed, decoupling self-association from cleavage.

    Evidence Domain mapping and protein-protein interaction assays on HCF-1 and HCF-2

    PMID:10958670

    Open questions at the time
    • Physiological role of unprocessed HCF-2 self-association unknown
    • Why HCF-2 escapes proteolysis not established
  3. 2001 Medium

    Defined a conserved WYF–MYND interaction with the negative regulator PDCD2 and asked whether it extends to HCF-2, noting conservation of the interaction across human HCF-2 and C. elegans HCF.

    Evidence Co-immunoprecipitation, reciprocal domain interaction mapping, and functional complementation with temperature-sensitive HCF-1 cells

    PMID:12149646

    Open questions at the time
    • PDCD2 regulation of HCF-2 inferred from conservation, not directly tested for HCF-2
    • Functional consequence of PDCD2 binding to HCF-2 unmeasured
  4. 2001 Medium

    Resolved whether HCFC2's stabilization of the VP16 complex translates into transcriptional output, demonstrating HCF-2 stabilizes the VP16-induced complex but fails to support transcriptional activation, separating complex assembly from activation function.

    Evidence In vitro complex assembly and transcriptional activation assays comparing HCF-1, HCF-2, and CeHCF

    PMID:11711630

    Open questions at the time
    • Molecular basis of activation deficiency not mapped
    • No identification of activation cofactors HCF-2 fails to recruit
  5. 2003 Medium

    Addressed post-translational and targeting regulation of HCF family members using CeHCF (structurally closer to HCF-2), mapping cell-cycle CDC2/CDK2 phosphorylation sites and showing a C-terminal signal sufficient to redirect HCF-2 into mitochondria.

    Evidence Phosphorylation-site mapping, cell-cycle synchronization, in vitro kinase assays, and GFP-fusion localization/domain-transfer experiments

    PMID:11341844 PMID:14629117

    Open questions at the time
    • Whether endogenous HCF-2 is phosphorylated or mitochondrially localized not shown
    • Functional significance of dual targeting unknown
  6. 2017 High

    Defined an in vivo physiological function distinct from the VP16 role, showing HCFC2 is required for IRF1/IRF2 binding at the Tlr3 promoter and for IRF2-dependent interferon-regulated gene expression, with loss causing viral susceptibility.

    Evidence ENU mutagenesis with three independent alleles, ChIP for IRF1/IRF2 promoter binding, macrophage cytokine assays, and in vivo influenza/HSV-1 infection survival

    PMID:28970238

    Open questions at the time
    • Direct biochemical interaction between HCFC2 and IRF1/IRF2 not shown
    • Mechanism by which HCFC2 promotes IRF promoter binding unresolved
    • Relationship between VP16 cofactor activity and IRF2 cofactor activity unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HCFC2's beta-propeller cofactor activity is mechanistically reconciled across its VP16/Oct-1 and IRF1/IRF2 roles, and what direct molecular partners mediate the immune function, remain unresolved.
  • No direct structural or biochemical link between HCFC2 and IRF transcription factors
  • Unknown whether transcription cofactor and chromatin recruitment mechanisms are shared with HCF-1

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-74160 Gene expression (Transcription) 2 R-HSA-168256 Immune System 1
Partners
IRF1IRF2PDCD2POU2F1VP16
Complex memberships
VP16-induced complex (VP16-Oct-1-DNA)

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 HCF-2 was identified as a second HCF-like protein sharing three regions of strong amino acid sequence homology with HCF-1, including the beta-propeller (kelch repeat) domain. HCF-2 associates with VP16 and can support complex assembly with Oct-1 and DNA, but is significantly less efficient than HCF-1. Chimeric protein analysis showed that differences between the fifth and sixth kelch repeats of the beta-propeller domains from HCF-1 and HCF-2 dictate this selectivity. HCF-2 shows a more dynamic pattern of subcellular localization than HCF-1 and is expressed especially in the testis. Sequence analysis, in vitro complex assembly assays, chimeric protein construction, subcellular localization studies Journal of virology High 10196288
2000 HCF-2, like HCF-1, contains a functional SAS1 self-association element (a short ~43-amino-acid region) in its N-terminal subunit. Unlike HCF-1, HCF-2 is not proteolyzed, yet still retains this association element, suggesting SAS1 does not function solely to maintain subunit association after cleavage. Domain mapping, protein-protein interaction assays, sequence analysis of HCF-1 and HCF-2 Molecular and cellular biology Medium 10958670
2001 The C-terminal WYF domain of HCF-1 interacts with the MYND domain of PDCD2, and this interaction is conserved between human HCF-2 and C. elegans HCF. Overexpression of PDCD2 suppresses HCF-1 complementation of a temperature-sensitive cell-cycle lesion, and overexpression of interfering domains of either PDCD2 or HCF-1 enhances complementation, establishing PDCD2 as a negative regulator of HCF-1 (and by conservation, HCF-2). Co-immunoprecipitation, domain interaction mapping, functional complementation assay with temperature-sensitive HCF-1 mutant cells Oncogene Medium 12149646
2001 All three HCF family members (HCF-1, HCF-2, and C. elegans CeHCF) can promote VP16-induced complex formation, indicating VP16 targets a highly conserved function. However, unlike HCF-1 and CeHCF, HCF-2 fails to support VP16 transcriptional activation effectively, demonstrating that HCF-2 can stabilize the VP16-induced complex but cannot mediate its transcriptional activity. In vitro complex assembly, transcriptional activation assays comparing HCF-1, HCF-2, and CeHCF Journal of virology Medium 11711630
2003 C. elegans CeHCF (which is structurally more related to HCF-2 than HCF-1) undergoes developmental and cell-cycle-regulated phosphorylation. Phosphorylation occurs at four clustered CDC2/CDK2 consensus sites in a non-conserved region. Phosphorylation of CeHCF or human HCF-1 is dispensable for association with VP16. Phosphorylation-site mapping of endogenous CeHCF, cell-cycle synchronization experiments, in vitro kinase assays Biochemistry Medium 11341844
2003 A C-terminal targeting signal of CeHCF (last 23 amino acids) contains interdigitated amino acids involved in both nuclear and mitochondrial targeting. Critically, this signal is sufficient to redirect HCF-2 into mitochondria when transferred, demonstrating that HCF-2 can be targeted to mitochondria via a heterologous signal. GFP fusion constructs, live imaging in transgenic worms and mammalian cells, domain deletion/transfer experiments European journal of cell biology Medium 14629117
2017 HCFC2 is required for IRF1- and IRF2-dependent transcription of Tlr3 in macrophages. Three independent ENU-induced mutations in Hcfc2 specifically abrogated macrophage responses to poly(I:C). HCFC2 promotes binding of IRF1 and IRF2 to the Tlr3 promoter; without this, inflammatory cytokine and type I IFN responses are reduced. HCFC2 is also necessary for transcription of a large subset of other IRF2-dependent interferon-regulated genes. Hcfc2 mutations compromised survival during influenza virus and herpes simplex virus 1 infections in mice. ENU mutagenesis screen, chromatin immunoprecipitation (ChIP) showing IRF1/IRF2 binding to Tlr3 promoter, cytokine response assays in macrophages, in vivo infection survival experiments The Journal of experimental medicine High 28970238

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Genetic dissection of behavioral flexibility: reversal learning in mice. Biological psychiatry 84 21392734
2001 In situ X-ray diffraction and solid-state NMR study of the fluorination of gamma-Al(2)O(3) with HCF(2)Cl. Journal of the American Chemical Society 49 11456769
1999 Isolation and characterisation of five different hydrophobin-encoding cDNAs from the fungal tomato pathogen Cladosporium fulvum. Molecular & general genetics : MGG 45 10394901
2001 The hydrophobin HCf-1 of Cladosporium fulvum is required for efficient water-mediated dispersal of conidia. Fungal genetics and biology : FG & B 44 11343402
2000 Stability of transferred human chromosome fragments in cultured cells and in mice. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 43 11196134
2002 PDCD2 is a negative regulator of HCF-1 (C1). Oncogene 42 12149646
2000 HCF-1 amino- and carboxy-terminal subunit association through two separate sets of interaction modules: involvement of fibronectin type 3 repeats. Molecular and cellular biology 42 10958670
2022 Differential microRNA expression analyses across two brain regions in Alzheimer's disease. Translational psychiatry 40 36038535
1999 Herpes simplex virus transactivator VP16 discriminates between HCF-1 and a novel family member, HCF-2. Journal of virology 40 10196288
2022 Comprehensive genomic analysis of refractory multiple myeloma reveals a complex mutational landscape associated with drug resistance and novel therapeutic vulnerabilities. Haematologica 29 35045690
2019 Construction of Difluoromethylated Tetrazoles via Silver-Catalyzed Regioselective [3 + 2] Cycloadditions of Aryl Diazonium Salts. Organic letters 26 31184157
2017 Esterification of Carboxylic Acids with Difluoromethyl Diazomethane and Interrupted Esterification with Trifluoromethyl Diazomethane: A Fluorine Effect. Organic letters 21 28981298
1983 Characterization of Nuclear Mutants of Maize Which Lack the Cytochrome f/b-563 Complex. Plant physiology 21 16663238
2017 HCFC2 is needed for IRF1- and IRF2-dependent Tlr3 transcription and for survival during viral infections. The Journal of experimental medicine 20 28970238
2021 Residue-Selective Protein C-Formylation via Sequential Difluoroalkylation-Hydrolysis. ACS central science 18 33532577
2001 Developmental and cell-cycle regulation of Caenorhabditis elegans HCF phosphorylation. Biochemistry 17 11341844
2001 Stabilization but not the transcriptional activity of herpes simplex virus VP16-induced complexes is evolutionarily conserved among HCF family members. Journal of virology 17 11711630
2023 Electrochemical Difluoromethylation of Electron-Rich Olefins. Organic letters 16 36867562
2022 Electrochemical-Oxidation-Promoted Direct N-ortho-Selective Difluoromethylation of Heterocyclic N-Oxides. Organic letters 15 35166558
2021 Defluorination of Omega-Hydroperfluorocarboxylates (ω-HPFCAs): Distinct Reactivities from Perfluoro and Fluorotelomeric Carboxylates. Environmental science & technology 14 34618445
2003 Molecular cloning of Drosophila HCF reveals proteolytic processing and self-association of the encoded protein. Journal of cellular physiology 13 12494450
2020 Development and validation of a nomogram with an epigenetic signature for predicting survival in patients with lung adenocarcinoma. Aging 11 33221751
2011 Novel fluorous amphiphilic heteroleptic Ru-based complexes for a dye-sensitized solar cell: the first fluorous bis-ponytailed amphiphilic Ru complexes. Inorganic chemistry 9 21491926
2008 Characterization of the glycosylphosphatidylinositol-anchor signal sequence of human Cryptic with a hydrophilic extension. Biochimica et biophysica acta 9 18930707
2008 Localization of Cladosporium fulvum hydrophobins reveals a role for HCf-6 in adhesion. FEMS microbiology letters 9 18958901
2003 Primary structure and compartmentalization of Drosophila melanogaster host cell factor. Gene 6 12609738
2023 Synthesis of Fluoromethylated Chromones and Their Heteroatom Analogues via Sodium Fluoromethanesulfinate-Enabled Direct Fluoromethylation. The Journal of organic chemistry 4 38115769
2003 A C-terminal targeting signal controls differential compartmentalisation of Caenorhabditis elegans host cell factor (HCF) to the nucleus or mitochondria. European journal of cell biology 4 14629117
2023 The preparation of difluoromethylated indoles via electrochemical oxidation under catalyst- and oxidant-free conditions. Organic & biomolecular chemistry 3 37183760
2022 Establishing a Macrophage Phenotypic Switch-Associated Signature-Based Risk Model for Predicting the Prognoses of Lung Adenocarcinoma. Frontiers in oncology 3 35284334
2018 Hydrogen bonding and fluorous weak interactions in the non-isomorphous {4,4'-bis[(2,2,3,3-tetrafluoropropoxy)methyl]-2,2'-bipyridine-κ2N,N'}dibromidopalladium and -platinum complexes. Acta crystallographica. Section C, Structural chemistry 3 29870013

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