Affinage

HADHB

Trifunctional enzyme subunit beta, mitochondrial · UniProt P55084

Length
474 aa
Mass
51.3 kDa
Annotated
2026-06-10
35 papers in source corpus 16 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HADHB encodes the β-subunit of the mitochondrial trifunctional protein (MTP), an α4β4 hetero-octamer that carries out the long-chain 3-ketoacyl-CoA thiolase (LCTH) step in the final stage of mitochondrial fatty acid β-oxidation, with the HADHA α-subunit providing the upstream enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activities (PMID:9259266, PMID:9605857). Compound heterozygous HADHB mutations can produce isolated LCTH deficiency with near-absent thiolase activity but preserved LCHAD activity, establishing that the β-subunit specifically supplies the thiolase catalytic function within MTP (PMID:16423905); other disease-associated missense substitutions compromise MTP complex stability and lower mutant protein levels in a temperature-sensitive manner, defining a loss-of-function/instability basis for the resulting neuromyopathic and MTP-deficiency phenotypes (PMID:31521624). Beyond catalysis, HADHB is a mitochondrial RNA-binding protein: it binds an AU-rich element in the REN mRNA 3'-UTR and destabilizes renin transcripts in a manner sensitive to a thiolase inhibitor (PMID:12933794), and it binds precursor 14q32 microRNAs to support maturation of miR-329 and miR-495 after precursor formation (PMID:30665182). Its β-oxidation activity is modulated by direct mitochondrial interactions with estrogen receptors, with ERα activating and ERβ inhibiting HADHB thiolase activity (PMID:22375075, PMID:23000159), and by MALAT1 lncRNA, which enhances thiolase activity to sustain fatty acid oxidation and restrain pro-inflammatory macrophage activation (PMID:41816300). HADHB expression is set transcriptionally by ZNF460 and by glucocorticoid-receptor signaling, and epigenetically by promoter methylation, linking its level to fatty acid metabolism in tumor and immune contexts (PMID:38865940, PMID:40404004, PMID:41918496); its loss triggers an ATF6/eIF2α/CHOP ER-stress axis that mediates lung tumor suppression (PMID:42179784).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1997 High

    Established the molecular identity and architecture of HADHB, answering which catalytic step of long-chain β-oxidation it provides and how it relates to its partner subunit.

    Evidence Genomic mutational analysis, FISH mapping, and enzyme activity assays in patient fibroblasts defining HADHB as the thiolase-bearing β-subunit of the α4β4 MTP

    PMID:9259266 PMID:9605857

    Open questions at the time
    • No experimental structure of the assembled MTP at this stage
    • Regulation of complex assembly not addressed
  2. 2003 Medium

    Revealed an unexpected moonlighting role: HADHB binds REN mRNA and destabilizes it, separating a metabolic enzyme's catalytic surface from a post-transcriptional regulatory function.

    Evidence Yeast three-hybrid screen, recombinant RNA-binding assay, RNAi knockdown, co-IP/RT-PCR, and thiolase-inhibitor experiments

    PMID:12933794

    Open questions at the time
    • Single lab; physiological relevance to renin regulation in vivo unproven
    • Structural basis for AU-rich element recognition unknown
  3. 2006 High

    Demonstrated that HADHB mutation alone causes isolated LCTH deficiency, formally assigning the thiolase activity of MTP to the β-subunit.

    Evidence Separate LCTH and LCHAD enzyme assays plus mutation analysis in patient fibroblasts

    PMID:16423905

    Open questions at the time
    • Genotype–phenotype correlation across mutation spectrum not resolved
  4. 2012 High

    Showed that estrogen receptors directly bind HADHB in mitochondria and bidirectionally tune its β-oxidation activity, defining hormone-responsive control of the thiolase.

    Evidence Affinity purification/MS, reciprocal co-IP from purified mitochondria, in vitro binding, confocal microscopy, and enzyme activity assays for ERα; co-IP, confocal, siRNA, and activity assays for ERβ

    PMID:22375075 PMID:23000159

    Open questions at the time
    • Mechanism by which ER binding alters thiolase activity unresolved
    • Significance outside breast cancer cell lines not established
  5. 2018 Medium

    Extended HADHB's RNA-binding repertoire to precursor miRNAs, implicating it in post-transcriptional maturation of 14q32 microRNAs.

    Evidence RNA pull-down SILAC mass spectrometry and CRISPR/Cas9 knockout measuring mature versus precursor miR-329/miR-495

    PMID:30665182

    Open questions at the time
    • Direct enzymatic role in miRNA processing not defined
    • Whether thiolase activity is required for this function unknown
  6. 2019 Medium

    Connected HADHB loss-of-function to organismal and cellular phenotypes, clarifying both neuronal requirement and the instability mechanism of disease mutations.

    Evidence Neuron-specific RNAi in Drosophila with behavioral/NMJ/ATP/ROS readouts; temperature-shift and localization studies of M136T/A141T in patient cells

    PMID:30953623 PMID:31521624

    Open questions at the time
    • Drosophila phenotypes not mechanistically tied to specific human mutations
    • Link between complex instability and neuromyopathy at molecular level incomplete
  7. 2025 Medium

    Defined upstream and downstream nodes placing HADHB in tumor metabolism: ZNF460 and promoter methylation set its expression, and a HADHB–DUOX2–ROS axis modulates chemosensitivity.

    Evidence ChIP-qPCR/dual-luciferase for ZNF460; cadmium-induced TET2-dependent promoter hypermethylation; co-IP and DUOX2 rescue of ROS in CRC cells

    PMID:38865940 PMID:40404004 PMID:40875107

    Open questions at the time
    • Whether thiolase catalysis or scaffolding drives the ROS/chemosensitivity effects unclear
    • Each axis shown in a single cancer context
  8. 2026 Medium

    Positioned HADHB within stress and immunometabolic signaling, with ER-stress/CHOP mediating tumor suppression and MALAT1/GR controlling macrophage fatty acid oxidation.

    Evidence Hadhb knockout K-Ras mouse with Chop-knockdown rescue; RIP and thiolase activity for MALAT1; GR/dual-luciferase for the GCK–GR–HADHB axis in UC models

    PMID:41816300 PMID:41918496 PMID:42179784

    Open questions at the time
    • How loss of a metabolic enzyme triggers the ATF6/eIF2α/CHOP axis mechanistically unclear
    • Each finding from a single lab/model

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HADHB partitions between its canonical thiolase catalysis and its RNA-binding/scaffolding moonlighting roles, and whether these are mechanistically coupled, remains unresolved.
  • No structure of HADHB bound to RNA or to ER/DUOX2/MALAT1 partners
  • Whether catalytic and non-catalytic functions share or use distinct surfaces is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0016740 transferase activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-1430728 Metabolism 2
Partners
DUOX2ESR1ESR2HADHAMALAT1
Complex memberships
Mitochondrial trifunctional protein (MTP)

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 The HADHB gene encodes the β-subunit of the mitochondrial trifunctional protein (MTP), an α4β4 hetero-octameric complex; HADHB contains the 3-ketoacyl-CoA thiolase domain while the α-subunit (HADHA) contains enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase domains. The two genes (HADHA and HADHB) co-map to chromosome band 2p23 and are adjacently located, similar to bacterial fatty acid β-oxidation multienzyme complex subunit gene organization. Genomic mutational analysis, FISH mapping, biochemical enzyme activity assays in patient fibroblasts Human molecular genetics / Cytogenetics and cell genetics High 9259266 9605857
2003 HADHB protein binds specifically to a 34-nucleotide AU-rich 'renin stability regulatory element' in the 3'-UTR of REN mRNA and acts as a destabilizer of renin mRNA: RNAi-mediated knockdown of HADHB increased renin mRNA stability and renin protein levels, while a specific thiolase inhibitor (4-bromocrotonic acid) decreased HADHB binding to the 3'-UTR and elevated renin protein. HADHB was confirmed to associate with REN mRNA in vivo by immunoprecipitation/RT-PCR and localizes to mitochondria by intracellular imaging. Yeast three-hybrid screening, recombinant protein RNA-binding assay, RNAi knockdown, immunoprecipitation/RT-PCR, intracellular imaging, reporter construct transfection The Journal of biological chemistry Medium 12933794
2006 Mutations in HADHB alone (compound heterozygous R62H and F431S) can cause isolated long-chain ketoacyl-CoA thiolase (LCTH) deficiency with near-absent LCTH activity (4% of normal) and normal LCHAD activity, establishing that HADHB encodes specifically the LCTH catalytic function within MTP. Enzyme activity assays (LCTH and LCHAD measured separately), molecular mutation analysis of patient fibroblasts Clinical chemistry High 16423905
2012 Estrogen receptor alpha (ERα) directly binds to HADHB in mitochondria: interaction was verified by affinity purification/proteomics, co-immunoprecipitation with whole-cell and purified mitochondrial extracts, in vitro binding assay, and co-localization by confocal microscopy. ERα expression modulates HADHB thiolase (β-oxidation) enzyme activity, and combined 17β-estradiol plus tamoxifen treatment affects the ERα–HADHB association and HADHB activity in ERα-positive but not ERα-negative breast cancer cells. Affinity purification/2D-gel/mass spectrometry, co-immunoprecipitation (whole cell and purified mitochondria), in vitro binding assay, confocal microscopy, enzyme activity assay, RNAi/pharmacological manipulation Molecular & cellular proteomics High 22375075
2012 Estrogen receptor beta (ERβ) also associates and co-localizes with HADHB within mitochondria, shown by co-immunoprecipitation and confocal microscopy in MCF7 cells. In contrast to ERα (which stimulates HADHB activity), ERβ silencing enhanced HADHB enzyme activity, indicating an inhibitory role of ERβ on HADHB β-oxidation activity. Co-immunoprecipitation, confocal microscopy, siRNA silencing, enzyme activity assay Biochemical and biophysical research communications Medium 23000159
2014 Structural analysis of the HADHB β-subunit showed that disease-associated missense mutations (A392V and the previously reported N389D) are located near the active site of MTP and affect conformation of the β-subunit, providing a structural basis for MTP deficiency with hypoparathyroidism and peripheral polyneuropathy. Structural modeling/analysis of mutation positions relative to active site, biochemical analysis confirming MTP deficiency, HADHB sequencing American journal of medical genetics. Part A Low 24664533
2018 HADHB protein binds to precursor microRNAs (pre-miR-329, pre-miR-495) as identified by RNA pull-down SILAC mass spectrometry. HADHB knockout (CRISPR/Cas9) in 3T3 cells reduced expression of mature miR-329 and miR-495 but not their precursors, suggesting HADHB plays a role in posttranscriptional processing of 14q32 microRNAs after precursor formation. RNA pull-down SILAC mass spectrometry, CRISPR/Cas9 knockout, RBP immunoprecipitation, immunohistochemistry Molecular therapy. Nucleic acids Medium 30665182
2019 Neuron-specific knockdown of Drosophila HADHB (dHADHB/CG4581) reduced locomotor ability, shortened lifespan, impaired learning, caused abnormal neuromuscular junction (NMJ) synapse morphology, and reduced both ATP and ROS levels in the CNS, establishing a critical role for HADHB in glutamatergic neuron morphogenesis and function. Neuron-specific RNAi knockdown in Drosophila, behavioral assays (lifespan, locomotion, learning), NMJ morphology analysis, ATP and ROS measurement Experimental cell research Medium 30953623
2019 HADHB mutations M136T and A141T (compound heterozygous) compromise MTP complex stability but do not alter subcellular localization of HADHB; mutant protein levels are lower at 37°C but partially restored at 30°C (temperature-sensitive), establishing a loss-of-function/instability mechanism for the mild neuromyopathic phenotype. In vitro cell functional studies, immunoblotting, subcellular localization analysis, temperature-shift experiments in patient-derived cells Mitochondrion Medium 31521624
2024 Chronic cadmium exposure leads to hypermethylation of the HADHB promoter region via inhibition of the DNA demethylase TET2, resulting in decreased HADHB expression, activation of the FAK signaling pathway, and enhanced CRC cell migration and invasion. RNA-seq, qRT-PCR, tissue microarray, chromatin/promoter methylation analysis, in vitro migration/invasion assays, in vivo lung metastasis model Ecotoxicology and environmental safety Medium 38865940
2025 HADHB interacts with DUOX2 (identified by co-immunoprecipitation); knockdown of HADHB in CRC cells improved 5-FU sensitivity and reduced ROS production, while DUOX2 overexpression reversed the ROS reduction caused by HADHB knockdown, establishing a functional HADHB–DUOX2–ROS axis that modulates 5-FU chemosensitivity. Co-immunoprecipitation, CCK-8, flow cytometry (apoptosis, cell cycle), siRNA knockdown, overexpression, ROS measurement, metabolomics/transcriptomics Discover oncology Medium 40875107
2025 ZNF460 transcription factor activates HADHB transcription: ChIP-qPCR and dual-luciferase reporter assays demonstrated ZNF460 binding to the HADHB promoter and transcriptional upregulation, with downstream effects on fatty acid metabolism and CTCL tumor progression and pulmonary invasion. ChIP-qPCR, dual-luciferase reporter assay, siRNA knockdown, overexpression, in vivo tumor model Archives of biochemistry and biophysics Medium 40404004
2026 HADHB loss induces ER stress (increased ATF6(N), phospho-eIF2α, and upregulated CHOP), and CHOP knockdown partially restores oncogenic potential in Hadhb-deficient mice and rescues growth defects of HADHB-depleted cells, establishing CHOP as a key downstream mediator of a HADHB–ER stress–CHOP axis in lung tumor suppression. Hadhb knockout mouse model with K-Ras G12D-driven lung tumors, immunoblotting for ER stress markers, Chop knockdown rescue experiments, cell proliferation and apoptosis assays Journal of Cancer Medium 42179784
2026 MALAT1 lncRNA interacts with HADHB protein and enhances its thiolase activity during the late phase of macrophage inflammation; this interaction is facilitated by HuR-MTCH2-mediated mitochondrial targeting of MALAT1. MALAT1 knockdown causes metabolic reprogramming (enhanced glycolysis, increased fatty acid synthesis, reduced FAO) and augments pro-inflammatory macrophage activation, placing HADHB as a mediator of MALAT1's metabolic and anti-inflammatory effects. RNA immunoprecipitation, thiolase activity assay, MALAT1 knockdown, metabolic flux measurements (glycolysis, FAO, fatty acid synthesis), macrophage activation assays iScience Medium 41816300
2026 Ginsenoside compound K (GCK) activates glucocorticoid receptor (GR/NR3C1) to upregulate HADHB expression (confirmed by dual-luciferase reporter assay), promoting fatty acid oxidation in macrophages and restoring M1/M2 macrophage polarization balance in ulcerative colitis models, placing HADHB downstream of GR signaling in macrophage metabolic reprogramming. Dual-luciferase reporter assay, western blot, RT-qPCR, flow cytometry, DSS-induced UC mouse model, LPS-stimulated RAW264.7 cells, metabolite detection British journal of pharmacology Medium 41918496

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 HADHB, HuR, and CP1 bind to the distal 3'-untranslated region of human renin mRNA and differentially modulate renin expression. The Journal of biological chemistry 54 12933794
2012 Estrogen receptor alpha interacts with mitochondrial protein HADHB and affects beta-oxidation activity. Molecular & cellular proteomics : MCP 52 22375075
2006 Isolated mitochondrial long-chain ketoacyl-CoA thiolase deficiency resulting from mutations in the HADHB gene. Clinical chemistry 51 16423905
1997 Genomic and mutational analysis of the mitochondrial trifunctional protein beta-subunit (HADHB) gene in patients with trifunctional protein deficiency. Human molecular genetics 47 9259266
2011 Comprehensive cDNA study and quantitative analysis of mutant HADHA and HADHB transcripts in a French cohort of 52 patients with mitochondrial trifunctional protein deficiency. Molecular genetics and metabolism 46 21549624
2018 Integrated analyses of multi-omics reveal global patterns of methylation and hydroxymethylation and screen the tumor suppressive roles of HADHB in colorectal cancer. Clinical epigenetics 34 29507648
2007 Identification of novel mutations of the HADHA and HADHB genes in patients with mitochondrial trifunctional protein deficiency. International journal of molecular medicine 30 17143551
2014 Mutations in HADHB, which encodes the β-subunit of mitochondrial trifunctional protein, cause infantile onset hypoparathyroidism and peripheral polyneuropathy. American journal of medical genetics. Part A 29 24664533
2021 MTP deficiency caused by HADHB mutations: Pathophysiology and clinical manifestations. Molecular genetics and metabolism 27 33744096
2019 HADHA and HADHB gene associated phenotypes - Identification of rare variants in a patient cohort by Next Generation Sequencing. Molecular and cellular probes 25 30682426
2013 A compound heterozygous mutation in HADHB gene causes an axonal Charcot-Marie-tooth disease. BMC medical genetics 25 24314034
2019 Expression of miR-33 from an SREBP2 intron inhibits the expression of the fatty acid oxidation-regulatory genes CROT and HADHB in chicken liver. British poultry science 24 30698464
2018 Posttranscriptional Regulation of 14q32 MicroRNAs by the CIRBP and HADHB during Vascular Regeneration after Ischemia. Molecular therapy. Nucleic acids 24 30665182
2012 Estrogen receptor beta interacts and colocalizes with HADHB in mitochondria. Biochemical and biophysical research communications 24 23000159
2019 MtpB, a member of the MttB superfamily from the human intestinal acetogen Eubacterium limosum, catalyzes proline betaine demethylation. The Journal of biological chemistry 23 31341018
2015 Mitochondrial trifunctional protein deficiency due to HADHB gene mutation in a Chinese family. Molecular genetics and metabolism reports 13 28649548
2011 A patient with mitochondrial trifunctional protein deficiency due to the mutations in the HADHB gene showed recurrent myalgia since early childhood and was diagnosed in adolescence. Molecular genetics and metabolism 13 22000755
2019 Neuron-specific knockdown of Drosophila HADHB induces a shortened lifespan, deficient locomotive ability, abnormal motor neuron terminal morphology and learning disability. Experimental cell research 12 30953623
2009 Two novel HADHB gene mutations in a Korean patient with mitochondrial trifunctional protein deficiency. Annals of clinical and laboratory science 12 19880769
1997 Fluorescence in situ hybridization mapping of the alpha and beta subunits (HADHA and HADHB) of human mitochondrial fatty acid beta-oxidation multienzyme complex to 2p23 and their evolution. Cytogenetics and cell genetics 11 9605857
2024 DNA demethylase TET2-mediated reduction of HADHB expression contributes to cadmium-induced malignant progression of colorectal cancer. Ecotoxicology and environmental safety 9 38865940
2018 HADHB mutations cause infantile-onset axonal Charcot-Marie-Tooth disease: A report of two cases. Clinical neuropathology 9 29956646
2019 Identification and functional characterization of mutations within HADHB associated with mitochondrial trifunctional protein deficiency. Mitochondrion 6 31521624
2022 Novel mutations in the HADHB gene causing a mild phenotype of mitochondrial trifunctional protein (MTP) deficiency. JIMD reports 4 35433169
2017 Identification of a Novel HADHB Gene Mutation in an Iranian Patient with Mitochondrial Trifunctional Protein Deficiency. Archives of Iranian medicine 4 28112527
2020 Novel HADHB mutations in a patient with mitochondrial trifunctional protein deficiency. Human genome variation 3 32257295
2025 The Role of HADHB in Mitochondrial Fatty Acid Metabolism During Initiation of Metastasis in ccRCC. Molecular carcinogenesis 2 39991877
2026 MALAT1 regulates human macrophage metabolism by interacting with HADHB. iScience 0 41816300
2026 Ginsenoside compound K up-regulates β-subunits of long-chain L-3-hydroxyacyl-CoA (HADHB) to promote fatty acid oxidation recovery and improve the balance of macrophage polarization in mice with ulcerative colitis. British journal of pharmacology 0 41918496
2026 Hadhb Deficiency Inhibits Lung Tumorigenesis Via Activating ER Stress. Journal of Cancer 0 42179784
2025 Mechanisms of adipocyte regulation: Insights from HADHB gene modulation. PloS one 0 40146690
2025 ZNF460 enhances HADHB level by activating its transcription to promote the progression and pulmonary invasion of cutaneous T cell lymphoma. Archives of biochemistry and biophysics 0 40404004
2025 HADHB mediates 5-fluorouracil sensitivity in colorectal cancer. Discover oncology 0 40875107
2024 Polymorphisms of CYP7A1 and HADHB Genes and Their Effects on Milk Production Traits in Chinese Holstein Cows. Animals : an open access journal from MDPI 0 38731280
2023 Case report: Mitochondrial trifunctional protein deficiency caused by HADHB gene mutation (c.1175C>T) characterized by higher brain dysfunction followed by neuropathy, presented gadolinium enhancement on brain imaging in an adult patient. Frontiers in neurology 0 37388542

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