Affinage

BBOX1

Gamma-butyrobetaine dioxygenase · UniProt O75936

Length
387 aa
Mass
44.7 kDa
Annotated
2026-06-09
100 papers in source corpus 4 papers cited in narrative 4 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BBOX1 (gamma-butyrobetaine hydroxylase 1) catalyzes the rate-limiting final step of de novo L-carnitine biosynthesis in humans, as demonstrated by a homozygous deletion that abolishes endogenous carnitine production while leaving dietary intake and renal reabsorption to compensate (PMID:24986124). Beyond its metabolic role, BBOX1 physically binds the ER calcium channel IP3R3 in an enzymatic-activity-dependent manner and shields it from ubiquitination and proteasomal degradation; loss of BBOX1 collapses IP3R3-mediated ER calcium release, calcium-dependent mitochondrial respiration, and mTORC1-driven glycolysis, triggering apoptosis and cell-cycle arrest in triple-negative breast cancer cells (PMID:32690540). BBOX1 itself is controlled post-translationally: it is ubiquitinated at K240 by a CRIP1/STUB1 E3 ligase complex, and this degradation lowers carnitine and acetylcarnitine, reducing beta-catenin acetylation and promoting nuclear beta-catenin accumulation to drive hepatocellular carcinoma stem-like properties (PMID:35775648). The gene is transcribed from three tissue-specific promoters (kidney, liver, brain) with alternative polyadenylation (PMID:17110165).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2006 Medium

    Established the genomic architecture and tissue-specific expression control of BBOX1, showing it is regulated by three distinct organ-specific promoters rather than a single transcriptional unit.

    Evidence 5'/3'-RACE, RT-PCR, Northern blot, and promoter mapping across kidney, liver, and brain

    PMID:17110165

    Open questions at the time
    • Does not establish the transcription factors driving each promoter
    • No functional consequence assigned to the alternative 3'-UTR isoforms
  2. 2014 Medium

    Defined the physiological consequence of complete BBOX1 loss in humans, confirming it as the rate-limiting enzyme of de novo carnitine synthesis but showing dietary and renal compensation prevents overt deficiency.

    Evidence Array CGH identifying a homozygous deletion plus serum carnitine/acylcarnitine profiling in a single patient

    PMID:24986124

    Open questions at the time
    • Single patient with no experimental reconstitution
    • Does not address tissue-level carnitine deficits in organs reliant on local synthesis
  3. 2020 High

    Revealed a moonlighting, metabolism-independent scaffolding function: BBOX1 stabilizes the IP3R3 calcium channel to sustain ER-to-mitochondria calcium signaling and mTORC1-driven glycolysis, defining a cancer dependency.

    Evidence Reciprocal Co-IP, siRNA knockdown with calcium-flux/respiration/mTORC1/apoptosis readouts, pharmacologic inhibition in vitro and in TNBC xenografts

    PMID:32690540

    Open questions at the time
    • Whether the BBOX1-IP3R3 interaction is direct or bridged is not resolved
    • Structural basis of the activity-dependent binding not determined
  4. 2022 High

    Identified how BBOX1 levels are set post-translationally and linked carnitine metabolism to oncogenic transcription, via CRIP1/STUB1-mediated K240 ubiquitination feeding into beta-catenin acetylation.

    Evidence Co-IP defining the CRIP1/BBOX1/STUB1 complex, K240 mutagenesis, ubiquitination assays, metabolite and beta-catenin acetylation/localization readouts in HCC cells

    PMID:35775648

    Open questions at the time
    • Mechanism by which acetylcarnitine controls beta-catenin acetylation is not biochemically defined
    • Does not test whether this degradation pathway also governs the IP3R3-stabilizing function

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BBOX1's enzymatic and scaffolding functions are coordinated across normal tissues versus tumors, and whether its IP3R3 stabilization is direct, remains unresolved.
  • No structural model of BBOX1-IP3R3 binding
  • Unknown whether CRIP1/STUB1 regulation operates in non-cancer contexts

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 1 R-HSA-162582 Signal Transduction 1
Partners
CRIP1IP3R3STUB1
Complex memberships
CRIP1/BBOX1/STUB1 ubiquitination complex

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 BBOX1 physically binds the calcium channel inositol-1,4,5-trisphosphate receptor type 3 (IP3R3) in an enzymatic activity-dependent manner and prevents IP3R3 ubiquitination and proteasomal degradation. BBOX1 depletion suppresses IP3R3-mediated endoplasmic reticulum calcium release, impairing calcium-dependent mitochondrial respiration and mTORC1-mediated glycolysis, leading to apoptosis and impaired cell-cycle progression in triple-negative breast cancer (TNBC) cells. Co-immunoprecipitation (Co-IP), siRNA knockdown with functional readouts (calcium flux, mitochondrial respiration, mTORC1 activity, apoptosis, cell-cycle assays), pharmacologic inhibition in vitro and in vivo xenograft models Cancer discovery High 32690540
2022 CRIP1 interacts with BBOX1 and the E3 ubiquitin ligase STUB1, forming a complex that promotes BBOX1 ubiquitination at lysine 240 and subsequent proteasomal degradation. This CRIP1-mediated reduction of BBOX1 downregulates carnitine (and acetylcarnitine) levels, decreasing beta-catenin acetylation and promoting nuclear beta-catenin accumulation to facilitate hepatocellular carcinoma stem-like properties. Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K240 ubiquitination site), carnitine/acetylcarnitine metabolite measurement, beta-catenin acetylation and nuclear localization assays, loss-of-function and gain-of-function experiments in HCC cells The EMBO journal High 35775648
2006 The human BBOX1 gene (encoding gamma-butyrobetaine hydroxylase) is organized across multiple exons on chromosome 11, with transcription initiating from 3 different exons driven by 3 distinct promoters in an organ-specific manner (kidney, liver, brain). Alternative polyadenylation generates two 3'-UTR isoforms with tissue-specific distribution. 5'-RACE, 3'-RACE, RT-PCR, Northern blot, promoter mapping across kidney, liver, and brain tissues Biochimica et biophysica acta Medium 17110165
2014 Homozygous deletion of BBOX1 in a human patient results in completely defective de novo carnitine biosynthesis, manifesting as mildly decreased free serum carnitine but not clinical carnitine deficiency, demonstrating that BBOX1 enzymatic activity is the rate-limiting step of de novo carnitine biosynthesis in humans and that dietary intake and renal reabsorption can compensate for its absence. Array comparative genomic hybridization identifying homozygous 221 kb deletion encompassing BBOX1; serum carnitine and acylcarnitine metabolic profiling in the patient BMC medical genetics Medium 24986124

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 High mobility group 1 B-box mediates activation of human endothelium. Journal of internal medicine 286 12974876
2019 BBX16, a B-box protein, positively regulates light-induced anthocyanin accumulation by activating MYB10 in red pear. Plant biotechnology journal 216 30963689
2005 The contribution of RING and B-box 2 domains to retroviral restriction mediated by monkey TRIM5alpha. The Journal of biological chemistry 152 15897199
2020 Apple B-box protein BBX37 regulates jasmonic acid mediated cold tolerance through the JAZ-BBX37-ICE1-CBF pathway and undergoes MIEL1-mediated ubiquitination and degradation. The New phytologist 145 33119890
2018 A tomato B-box protein SlBBX20 modulates carotenoid biosynthesis by directly activating PHYTOENE SYNTHASE 1, and is targeted for 26S proteasome-mediated degradation. The New phytologist 144 30101463
2001 Two B or not two B? Overview of the rapidly expanding B-box family of proteins. Differentiation; research in biological diversity 142 11428128
2019 The B-box zinc finger protein MdBBX20 integrates anthocyanin accumulation in response to ultraviolet radiation and low temperature. Plant, cell & environment 141 30919454
2009 A B-box 2 surface patch important for TRIM5alpha self-association, capsid binding avidity, and retrovirus restriction. Journal of virology 137 19656869
2012 The rice B-box zinc finger gene family: genomic identification, characterization, expression profiling and diurnal analysis. PloS one 134 23118960
1989 Ribosomal RNA operon anti-termination. Function of leader and spacer region box B-box A sequences and their conservation in diverse micro-organisms. Journal of molecular biology 131 2479752
2018 B-BOX DOMAIN PROTEIN28 Negatively Regulates Photomorphogenesis by Repressing the Activity of Transcription Factor HY5 and Undergoes COP1-Mediated Degradation. The Plant cell 123 30099385
2008 The TRIM5alpha B-box 2 domain promotes cooperative binding to the retroviral capsid by mediating higher-order self-association. Journal of virology 119 18799578
1999 Interaction between composite elements in the napA promoter: both the B-box ABA-responsive complex and the RY/G complex are necessary for seed-specific expression. Plant molecular biology 117 10480393
2012 BZS1, a B-box protein, promotes photomorphogenesis downstream of both brassinosteroid and light signaling pathways. Molecular plant 116 22535582
2014 An apple B-box protein, MdCOL11, is involved in UV-B- and temperature-induced anthocyanin biosynthesis. Planta 110 25074586
1994 A novel gene encoding a B-box protein within the BRCA1 region at 17q21.1. Human molecular genetics 107 8069304
2018 Two B-Box Proteins Regulate Photomorphogenesis by Oppositely Modulating HY5 through their Diverse C-Terminal Domains. Plant physiology 101 29439209
2006 Solution structure of the RBCC/TRIM B-box1 domain of human MID1: B-box with a RING. Journal of molecular biology 95 16529770
2001 The B-box dominates SAP-1-SRF interactions in the structure of the ternary complex. The EMBO journal 86 11406578
2016 Mechanism of B-box 2 domain-mediated higher-order assembly of the retroviral restriction factor TRIM5α. eLife 85 27253059
2020 An Apple B-Box Protein MdBBX37 Modulates Anthocyanin Biosynthesis and Hypocotyl Elongation Synergistically with MdMYBs and MdHY5. Plant & cell physiology 84 31550006
2017 The B-Box Domain Protein BBX21 Promotes Photomorphogenesis. Plant physiology 83 29259103
2016 Genomic Organization, Phylogenetic and Expression Analysis of the B-BOX Gene Family in Tomato. Frontiers in plant science 81 27807440
1997 Molecular characterization of the B-box protein-protein interaction motif of the ETS-domain transcription factor Elk-1. The EMBO journal 66 9171356
2020 LncRNA BBOX1-AS1 upregulates HOXC6 expression through miR-361-3p and HuR to drive cervical cancer progression. Cell proliferation 65 32515533
2017 Genome-wide identification and expression analysis of the B-box gene family in the Apple (Malus domestica Borkh.) genome. Molecular genetics and genomics : MGG 64 29063961
2015 Molecular dynamics simulation reveals insights into the mechanism of unfolding by the A130T/V mutations within the MID1 zinc-binding Bbox1 domain. PloS one 57 25874572
2020 Identification of BBOX1 as a Therapeutic Target in Triple-Negative Breast Cancer. Cancer discovery 55 32690540
2022 CRIP1 suppresses BBOX1-mediated carnitine metabolism to promote stemness in hepatocellular carcinoma. The EMBO journal 54 35775648
2021 A poplar B-box protein PtrBBX23 modulates the accumulation of anthocyanins and proanthocyanidins in response to high light. Plant, cell & environment 53 34114251
2017 B-BOX genes: genome-wide identification, evolution and their contribution to pollen growth in pear (Pyrus bretschneideri Rehd.). BMC plant biology 53 28927374
2023 Two B-box proteins, PavBBX6/9, positively regulate light-induced anthocyanin accumulation in sweet cherry. Plant physiology 50 36930566
2019 Apple B-box factors regulate light-responsive anthocyanin biosynthesis genes. Scientific reports 47 31780719
2020 Genome-wide identification and analysis of B-BOX gene family in grapevine reveal its potential functions in berry development. BMC plant biology 42 32054455
2019 The B-box protein BBX19 suppresses seed germination via induction of ABI5. The Plant journal : for cell and molecular biology 40 31112314
2021 KLF5-induced BBOX1-AS1 contributes to cell malignant phenotypes in non-small cell lung cancer via sponging miR-27a-5p to up-regulate MELK and activate FAK signaling pathway. Journal of experimental & clinical cancer research : CR 39 33931086
2017 Genome-wide survey of B-box proteins in potato (Solanum tuberosum)-Identification, characterization and expression patterns during diurnal cycle, etiolation and de-etiolation. PloS one 37 28552939
2011 Function of B-BOX under shade. Plant signaling & behavior 37 21301219
2008 Structural analysis of B-Box 2 from MuRF1: identification of a novel self-association pattern in a RING-like fold. Biochemistry 37 18795805
2021 Genome-Wide Characterization of B-Box Gene Family and Its Roles in Responses to Light Quality and Cold Stress in Tomato. Frontiers in plant science 36 34290726
2019 Comparative analysis of B-BOX genes and their expression pattern analysis under various treatments in Dendrobium officinale. BMC plant biology 36 31182022
2014 Interplay between circadian rhythm, time of the day and osmotic stress constraints in the regulation of the expression of a Solanum Double B-box gene. Annals of botany 36 24562097
2006 Genomic structure, alternative maturation and tissue expression of the human BBOX1 gene. Biochimica et biophysica acta 36 17110165
2022 BBOX1-AS1 contributes to colorectal cancer progression by sponging hsa-miR-361-3p and targeting SH2B1. FEBS open bio 34 31984680
2020 B-box transcription factor 28 regulates flowering by interacting with constans. Scientific reports 34 33082412
2021 B-box protein BBX32 integrates light and brassinosteroid signals to inhibit cotyledon opening. Plant physiology 33 34618149
2018 Genome Identification of B-BOX Gene Family Members in Seven Rosaceae Species and Their Expression Analysis in Response to Flower Induction in Malus domestica. Molecules (Basel, Switzerland) 33 30021984
2018 A Rice B-Box Protein, OsBBX14, Finely Regulates Anthocyanin Biosynthesis in Rice. International journal of molecular sciences 33 30060460
2022 lncRNA BBOX1-AS1 silencing inhibits esophageal squamous cell cancer progression by promoting ferroptosis via miR-513a-3p/SLC7A11 axis. European journal of pharmacology 32 36216119
2023 The B-box transcription factor IbBBX29 regulates leaf development and flavonoid biosynthesis in sweet potato. Plant physiology 30 36377782
1998 The novel estrogen-responsive B-box protein (EBBP) gene is tamoxifen-regulated in cells expressing an estrogen receptor DNA-binding domain mutant. Molecular endocrinology (Baltimore, Md.) 30 9817599
2001 GOA, a novel gene encoding a ring finger B-box coiled-coil protein, is overexpressed in astrocytoma. Biochemical and biophysical research communications 27 11511098
2023 A B-box transcription factor OsBBX17 regulates saline-alkaline tolerance through the MAPK cascade pathway in rice. The New phytologist 26 38098211
1998 Transcriptional activity of RBCK1 protein (RBCC protein interacting with PKC 1): requirement of RING-finger and B-Box motifs and regulation by protein kinases. Biochemical and biophysical research communications 26 9642138
2022 B-Box Transcription Factor FaBBX22 Promotes Light-Induced Anthocyanin Accumulation in Strawberry (Fragaria × ananassa). International journal of molecular sciences 25 35887106
2021 MdBBX21, a B-Box Protein, Positively Regulates Light-Induced Anthocyanin Accumulation in Apple Peel. Frontiers in plant science 25 34868172
2020 LncRNA BBOX1-AS1 Aggravates the Development of Ovarian Cancer by Sequestering miR-361-3p to Augment PODXL Expression. Reproductive sciences (Thousand Oaks, Calif.) 24 33159291
2014 The effect of homozygous deletion of the BBOX1 and Fibin genes on carnitine level and acyl carnitine profile. BMC medical genetics 24 24986124
2021 Genome-wide identification and expression analysis of the B-box transcription factor gene family in grapevine (Vitis vinifera L.). BMC genomics 23 33781207
2023 BBOX1-AS1 Activates Hedgehog Signaling Pathway to Facilitate the Proliferation and Stemness of Esophageal Squamous Cell Carcinoma Cells via miR-506-5p/EIF5A/PTCH1 Axis. Current molecular pharmacology 22 36717994
2022 Long non-coding RNA BBOX1 antisense RNA 1 increases the apoptosis of granulosa cells in premature ovarian failure by sponging miR-146b. Bioengineered 22 35188872
2005 The mei-P26 gene encodes a RING finger B-box coiled-coil-NHL protein that regulates seizure susceptibility in Drosophilia. Genetics 22 15937125
2024 A truncated B-box zinc finger transcription factor confers drought sensitivity in modern cultivated tomatoes. Nature communications 21 39271661
2021 Genome-wide identification of B-box proteins and VvBBX44 involved in light-induced anthocyanin biosynthesis in grape (Vitis vinifera L.). Planta 21 33934247
2020 BBOX1-AS1 Accelerates Gastric Cancer Proliferation by Sponging miR-3940-3p to Upregulate BIRC5 Expression. Digestive diseases and sciences 21 32394331
2021 Comprehensive identification and expression analysis of B-Box genes in cotton. BMC genomics 20 34118883
2021 Genome-Wide Identification of the B-BOX Genes that Respond to Multiple Ripening Related Signals in Sweet Cherry Fruit. International journal of molecular sciences 19 33562756
2019 Bioinformatics-based discovery of the urinary BBOX1 mRNA as a potential biomarker of diabetic kidney disease. Journal of translational medicine 19 30819181
2024 A tomato B-box protein regulates plant development and fruit quality through the interaction with PIF4, HY5, and RIN transcription factors. Journal of experimental botany 18 38492237
2017 Expression analysis of genes encoding double B-box zinc finger proteins in maize. Functional & integrative genomics 18 28480497
2022 Long non-coding RNA BBOX1-antisense RNA 1 enhances cell proliferation and migration and suppresses apoptosis in oral squamous cell carcinoma via the miR-3940-3p/laminin subunit gamma 2 axis. Bioengineered 16 35506252
2014 MID1 catalyzes the ubiquitination of protein phosphatase 2A and mutations within its Bbox1 domain disrupt polyubiquitination of alpha4 but not of PP2Ac. PloS one 16 25207814
2022 An ethylene-responsive transcription factor and a B-box protein coordinate vegetative growth and photoperiodic flowering in chrysanthemum. Plant, cell & environment 15 36367211
2023 Characterization of the B-BOX gene family in pepper and the role of CaBBX14 in defense response against Phytophthora capsici infection. International journal of biological macromolecules 14 36958453
2022 Genome-Wide Characterization and Anthocyanin-Related Expression Analysis of the B-BOX Gene Family in Capsicum annuum L. Frontiers in genetics 14 35295945
2021 Genome-wide and expression analysis of B-box gene family in pepper. BMC genomics 14 34872495
2010 Leishmania-induced repression of selected non-coding RNA genes containing B-box element at their promoters in alternatively polarized M2 macrophages. Molecular and cellular biochemistry 14 21165676
2024 The B-box transcription factor BnBBX22.A07 enhances salt stress tolerance by indirectly activating BnWRKY33.C03. Plant, cell & environment 13 39189937
2023 BBOX1-AS1 mediates trophoblast cells dysfunction via regulating hnRNPK/GADD45A axis†. Biology of reproduction 13 36617174
2021 An Evolutionary Analysis of B-Box Transcription Factors in Strawberry Reveals the Role of FaBBx28c1 in the Regulation of Flowering Time. International journal of molecular sciences 13 34769196
2024 Genome-wide identification of B-box zinc finger (BBX) gene family in Medicago sativa and their roles in abiotic stress responses. BMC genomics 12 38267840
2022 LncRNA BBOX1-AS1 promotes pituitary adenoma progression via sponging miR-361-3p/E2F1 axis. Anti-cancer drugs 12 35324526
2024 Two B-box proteins orchestrate vegetative and reproductive growth in summer chrysanthemum. Plant, cell & environment 11 38629334
2022 Long non-coding RNA BBOX1-AS1 exacerbates esophageal squamous cell carcinoma development by regulating HOXB7/β-catenin axis. Experimental cell research 11 35351402
2022 Genome-Wide Identification of the B-Box Gene Family and Expression Analysis Suggests Their Potential Role in Photoperiod-Mediated β-Carotene Accumulation in the Endocarp of Cucumber (Cucumis sativus L.) Fruit. Genes 11 35456464
2021 BBOX1-AS1 Accelerates Nasopharyngeal Carcinoma Progression by Sponging miR-3940-3p and Enhancing KPNA2 Upregulation. Cancer management and research 11 34938119
2021 Genome-wide identification of Brassicaceae B-BOX genes and molecular characterization of their transcriptional responses to various nutrient stresses in allotetraploid rapeseed. BMC plant biology 10 34167468
2021 Genome-Wide Identification, Evolution, and Comparative Analysis of B-Box Genes in Brassica rapa, B. oleracea, and B. napus and Their Expression Profiling in B. rapa in Response to Multiple Hormones and Abiotic Stresses. International journal of molecular sciences 10 34638707
2012 BBH-LS: an algorithm for computing positional homologs using sequence and gene context similarity. BMC systems biology 10 23046607
2023 Regulation of tumorigenesis and ferroptosis in non-small cell lung cancer by a novel BBOX1-AS1/miR-326/PROM2 axis. Molecular and cellular biochemistry 9 37639200
2023 Genome-wide analysis of blueberry B-box family genes and identification of members activated by abiotic stress. BMC genomics 9 37789264
2022 B-box containing protein 1 from Malus domestica (MdBBX1) is involved in the abiotic stress response. PeerJ 9 35178298
2022 PpZAT5 suppresses the expression of a B-box gene PpBBX18 to inhibit anthocyanin biosynthesis in the fruit peel of red pear. Frontiers in plant science 9 36304405
2021 Clinical significance and effect of lncRNA BBOX1-AS1 on the proliferation and migration of lung squamous cell carcinoma. Oncology letters 9 34820016
2017 BBOX1 is down-regulated in maternal immune-activated mice and implicated in genetic susceptibility to human schizophrenia. Psychiatry research 9 29065368
1990 Saturation mutagenesis of the Drosophila tRNA(Arg) gene B-Box intragenic promoter element: requirements for transcription activation and stable complex formation. Nucleic acids research 9 2109308
2024 B-BOX proteins:Multi-layered roles of molecular cogs in light-mediated growth and development in plants. Journal of plant physiology 8 38754343
2023 Genome-Wide Characterization of B-Box Gene Family in Salvia miltiorrhiza. International journal of molecular sciences 8 36768475
2023 Long noncoding RNA BBOX1-AS1 increased radiotherapy sensitivity in colorectal cancer by stabilizing and activating PFK1. Translational oncology 8 37544035
2017 Light signaling differentially regulates the expression of group IV of the B-box zinc finger family. Plant signaling & behavior 8 28922622

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