Affinage

ATRAID

All-trans retinoic acid-induced differentiation factor · UniProt Q6UW56

Length
229 aa
Mass
24.7 kDa
Annotated
2026-06-09
37 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATRAID (APR3) is a glycosylated lysosomal/endosomal membrane protein that controls the cellular delivery and pharmacology of nitrogen-containing bisphosphonates (N-BPs) and acts as a negative regulator of cell proliferation (PMID:29745899, PMID:25839652, PMID:17524364). It forms a complex with the solute carrier SLC37A3 at the lysosome, and this complex is required to release endocytosed N-BPs from the lysosomal lumen into the cytosol so they can reach farnesyl diphosphate synthase in the mevalonate pathway (PMID:29745899). Loss of ATRAID blocks N-BP-mediated inhibition of protein prenylation and osteoclast function and renders both cells and mice resistant to alendronate, while patient-derived coding variants alter cellular N-BP sensitivity, establishing ATRAID as a determinant of bisphosphonate therapeutic response in osteoporosis models (PMID:32434850). Its predominant isoform localizes to cytoplasmic vesicles, the Golgi region, and recycling endosomes marked by LAMP1, LAMP2, and RAB11, consistent with a role in endolysosomal trafficking (PMID:37530719). Independently, ATRAID restrains the cell cycle: overexpression drives G1/S arrest via marked downregulation of Cyclin D1, an activity that depends on its transmembrane/intracellular domain (PMID:17524364), and it physically binds NELL-1 to suppress osteoblast proliferation and promote osteogenic differentiation and mineralization (PMID:21723284, PMID:31416616). Transcription of ATRAID is driven from two distinct promoters that are activated by NFAT and repressed by NFκB (PMID:17387583).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2007 Medium

    Established the first functional role for APR3 as a negative cell-cycle regulator and mapped the activity to a specific protein region, defining it as a membrane-anchored growth suppressor.

    Evidence FACS cell-cycle analysis with full-length and transmembrane/intracellular-domain-truncated APR3 plus Cyclin D1 Western blot in overexpressing cells

    PMID:17524364

    Open questions at the time
    • Mechanism by which the transmembrane/intracellular domain lowers Cyclin D1 not defined
    • Based on overexpression rather than endogenous loss-of-function
  2. 2007 Medium

    Resolved how APR3 expression is controlled, showing two independent promoters under opposing transcriptional regulators rather than alternative splicing.

    Evidence Reporter assays with sequential 5' deletion and site-directed mutation, plus constitutively active NFAT and NFκB constructs

    PMID:17387583

    Open questions at the time
    • Physiological stimuli engaging NFAT/NFκB at the promoters unknown
    • Which isoform each promoter drives not connected to function
  3. 2011 Medium

    Identified NELL-1 as a binding partner of APR3 and linked the interaction to osteoblast biology, extending APR3's anti-proliferative function to bone differentiation.

    Evidence Biopanning for partner identification, co-localization at the nuclear envelope, and RNAi knockdown with proliferation, differentiation, and mineralization assays in osteoblasts

    PMID:21723284

    Open questions at the time
    • Interaction shown by biopanning, not reciprocal Co-IP
    • Molecular basis of Cyclin D1 downregulation by NELL-1/APR3 unresolved
  4. 2015 Medium

    Defined the subcellular home of APR3, placing it in the lysosomal membrane and excluding the ER.

    Evidence Lysosome subcellular fractionation with Western blot and double immunofluorescence co-localization with LAMP1 and Lyso-Tracker Red

    PMID:25839652

    Open questions at the time
    • Topology and orientation in the lysosomal membrane not determined
    • Functional role at the lysosome not addressed in this study
  5. 2016 Low

    Extended APR3's growth-suppressive activity to cellular senescence, again dependent on its transmembrane/intracellular domain.

    Evidence Overexpression of full-length and truncated APR3 with SA-β-galactosidase, proliferation, and p53/p21 Western blot in ARPE-19 cells

    PMID:26934949

    Open questions at the time
    • Single overexpression-based study without loss-of-function confirmation
    • Link between senescence and the cell-cycle/Cyclin D1 pathway not mechanistically connected
  6. 2018 High

    Defined the core lysosomal function of ATRAID: a SLC37A3-containing complex required to deliver endocytosed N-BPs to their cytosolic mevalonate-pathway target, placing ATRAID upstream of N-BP action.

    Evidence Genome-wide CRISPRi screen, reciprocal co-immunoprecipitation, lysosomal localization, and loss-of-function rescue experiments

    PMID:29745899

    Open questions at the time
    • Biochemical mechanism of N-BP transport across the lysosomal membrane not resolved
    • Stoichiometry and structure of the ATRAID–SLC37A3 complex unknown
  7. 2018 Medium

    Reported an APR3–NRF2 interaction coupling APR3 to mitochondrial redox status, broadening its functions beyond the lysosome.

    Evidence Co-immunoprecipitation, knockdown/overexpression with ROS, oxygen consumption, ATP, and mitochondrial localization assays

    PMID:29792731

    Open questions at the time
    • Reported mitochondrial localization not reconciled with lysosomal localization from other studies
    • Direct vs. indirect nature of APR3 regulation of NRF2 nuclear translocation unclear
  8. 2019 Medium

    Confirmed the NELL-1/APR3 interaction by reciprocal Co-IP and demonstrated its osteogenic differentiation role in a second cell type.

    Evidence Reciprocal co-immunoprecipitation, double immunofluorescence, shRNA knockdown, alkaline phosphatase and mineralization assays in dental pulp cells

    PMID:31416616

    Open questions at the time
    • How a nuclear-envelope NELL-1/APR3 complex controls Cyclin D1 not mechanistically defined
    • Relationship between this interaction and the lysosomal N-BP function unknown
  9. 2020 High

    Established the in vivo and clinical relevance of ATRAID, showing it is required for alendronate efficacy and that human variants modulate N-BP sensitivity.

    Evidence ATRAID knockout mouse osteoporosis models, cellular prenylation and viability assays, and exome sequencing with functional validation of patient variants

    PMID:32434850

    Open questions at the time
    • Whether ATRAID variants predict bisphosphonate side effects clinically not established
    • Endogenous physiological substrate or ligand beyond N-BPs not identified
  10. 2023 Medium

    Resolved which isoform carries ATRAID function and refined its trafficking itinerary through recycling endosomes.

    Evidence Transfection of Myc-Flag-tagged isoforms, subcellular fractionation, and immunofluorescence co-localization with LAMP1, LAMP2, and RAB11

    PMID:37530719

    Open questions at the time
    • Functional consequence of N-glycosylation and RAB11-dependent recycling not tested
    • Fate and significance of the rapidly degraded isoform A unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ATRAID's lysosomal N-BP-transport function, its Cyclin D1-dependent cell-cycle/osteoblast role, and its NRF2/mitochondrial activity are mechanistically integrated within one protein remains unresolved.
  • No structural model of the ATRAID–SLC37A3 transport complex
  • No endogenous physiological cargo or ligand identified beyond N-BPs
  • Reconciliation of lysosomal, nuclear-envelope, and mitochondrial localizations not achieved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140313 molecular sequestering activity 1
Localization
GO:0005764 lysosome 3 GO:0005635 nuclear envelope 2 GO:0005739 mitochondrion 1 GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-1430728 Metabolism 2 R-HSA-1640170 Cell Cycle 1
Partners
NELL1NFE2L2SLC37A3
Complex memberships
ATRAID–SLC37A3 lysosomal complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 ATRAID forms a protein complex with SLC37A3 (solute carrier family 37 member A3), and both proteins localize to lysosomes. Together, they are required for releasing nitrogen-containing bisphosphonates (N-BPs) that have trafficked to lysosomes via fluid-phase endocytosis into the cytosol, enabling N-BPs to reach their molecular target (farnesyl diphosphate synthase) in the mevalonate pathway. CRISPRi genome-wide screen, co-immunoprecipitation, subcellular localization (lysosomal), loss-of-function rescue experiments eLife High 29745899
2020 ATRAID is required for alendronate-mediated inhibition of protein prenylation and osteoclast function. Loss of ATRAID confers selective resistance to N-BP-mediated cell viability loss. ATRAID-deficient mice have impaired therapeutic responses to alendronate in postmenopausal and senile osteoporosis models. Patient-derived nonsynonymous coding variants in ATRAID confer cellular hypersensitivity to N-BPs. Genome-wide studies in cells, ATRAID knockout mouse models (postmenopausal and senile osteoporosis), exome sequencing of patients with N-BP side effects, functional validation of patient variants in cellular assays, prenylation inhibition assays Science translational medicine High 32434850
2015 APR3 is a lysosomal membrane protein. Western blot of isolated lysosomes demonstrated APR3 is present in the lysosomal membrane fraction but not in the endoplasmic reticulum. Double immunofluorescence confirmed co-localization with lysosomal membrane protein LAMP1 and lysosomal marker Lyso-Tracker Red. Subcellular fractionation (lysosome isolation), Western blot, double immunofluorescence co-localization with LAMP1 and Lyso-Tracker Red Biochemical and biophysical research communications Medium 25839652
2023 ATRAID isoform C (Iso C) is the predominantly expressed isoform; it is N-glycosylated and localizes to cytoplasmic vesicles, near the plasma membrane, and in the Golgi area. It co-localizes with endosomal/lysosomal markers LAMP1 and LAMP2, and with RAB11, a GTPase associated with recycling endosomes implicated in vesicular trafficking. Isoform A is rapidly degraded; Isoform B protein was not detected. Transfection with Myc-Flag-tagged isoforms, subcellular fractionation, immunofluorescence, co-localization with LAMP1, LAMP2, and RAB11 FEBS open bio Medium 37530719
2007 APR3 overexpression causes G1/S cell cycle arrest accompanied by dramatic reduction in Cyclin D1 expression. The truncated form of APR3 (lacking the predicted transmembrane and intracellular domain) antagonizes this effect, indicating the transmembrane/intracellular domain is required for membrane localization and negative regulation of the cell cycle. FACS cell cycle analysis, overexpression of full-length and truncated APR3, indirect immunofluorescence for localization, Cyclin D1 Western blot Biochemical and biophysical research communications Medium 17524364
2007 APR3 has two transcripts driven by distinct promoters (not alternative splicing). Constitutively active NFAT enhances both APR3 promoter activities, with functional NFAT binding sites mapped between -96 bp and -47 bp. Constitutively active NFκB inhibits APR3 transcription. Reporter assay, PCR, sequential 5' promoter deletion, site-directed mutation of promoter, expression of constitutively active NFAT and NFκB mutants Molecular and cellular biochemistry Medium 17387583
2011 NELL-1 physically binds to APR3 (identified by biopanning). NELL-1 and APR3 co-localize on the nuclear envelope of human osteoblasts. NELL-1 inhibits osteoblast proliferation in cells co-transfected with APR3 through further downregulation of Cyclin D1. Co-expression of NELL-1 and APR3 enhances osteocalcin and bone sialoprotein expression and mineralization; RNAi of APR3 reduces the differentiation effect of NELL-1. Biopanning for binding partner identification, co-localization by immunofluorescence, co-transfection with RNAi knockdown, proliferation assay, differentiation/mineralization assays FEBS letters Medium 21723284
2019 Endogenous NELL-1 co-immunoprecipitates with APR3 reciprocally in human dental pulp cells. NELL-1 and APR3 co-localize on the nuclear envelope. NELL-1 inhibits proliferation of cells co-infected with APR3 through Cyclin D1 downregulation. The NELL-1/APR3 interaction stimulates alkaline phosphatase activity and promotes expression of DSPP, ALP, OPN, and BSP and mineralization; APR3 shRNA decreases differentiation and mineralization. Reciprocal co-immunoprecipitation, double immunofluorescence, shRNA knockdown, alkaline phosphatase activity assay, mineralization assay Biochemical and biophysical research communications Medium 31416616
2018 APR3 interacts with NRF2 (nuclear factor erythroid-derived 2-like 2). Knockdown of APR3 promotes NRF2 nuclear translocation and activates phase II enzyme expression, improving redox status and mitochondrial activity. Overexpression of APR3 induces reactive oxygen species production, impairs mitochondrial oxygen consumption and complex activity, reduces ATP content, and causes mitochondrial structural damage, contributing to apoptosis. APR3 overexpression reveals its mitochondrial localization. Co-immunoprecipitation (APR3–NRF2 interaction), knockdown and overexpression, ROS measurement, mitochondrial oxygen consumption assay, ATP content assay, immunofluorescence for mitochondrial localization FASEB journal Medium 29792731
2016 APR3 overexpression promotes cellular senescence in ARPE-19 cells, characterized by enhanced senescence-associated β-galactosidase activity, reduced proliferation, and increased expression of p53 and p21. Overexpression of a truncated APR3-N (lacking transmembrane/intracellular domain) abrogates APR3-induced senescent phenotypes. Overexpression of full-length and truncated APR3, senescence-associated β-galactosidase assay, proliferation assay, Western blot for p53 and p21 Molecular medicine reports Low 26934949

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Sulfate reduction in higher plants: molecular evidence for a novel 5'-adenylylsulfate reductase. Proceedings of the National Academy of Sciences of the United States of America 121 8917600
2018 Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates. eLife 43 29745899
2011 NELL-1 binds to APR3 affecting human osteoblast proliferation and differentiation. FEBS letters 34 21723284
2000 Improved PCR-based subtractive hybridization strategy for cloning differentially expressed genes. BioTechniques 31 10948432
2021 The Genetics of Atypical Femur Fractures-a Systematic Review. Current osteoporosis reports 25 33587247
2020 miR-144-3p Contributes to the Development of Thyroid Tumors Through the PTEN/PI3K/AKT Pathway. Cancer management and research 23 33116843
2020 ATRAID regulates the action of nitrogen-containing bisphosphonates on bone. Science translational medicine 20 32434850
2007 Identification of the distinct promoters for the two transcripts of apoptosis related protein 3 and their transcriptional regulation by NFAT and NFkappaB. Molecular and cellular biochemistry 19 17387583
2012 Brain transcriptome-wide screen for HIV-1 Nef protein interaction partners reveals various membrane-associated proteins. PloS one 16 23284715
2009 SV40 T antigen disrupted the cell metabolism and the balance between proliferation and apoptosis in lens tumors of transgenic mice. Journal of cancer research and clinical oncology 16 19466455
2016 Apr3 accelerates the senescence of human retinal pigment epithelial cells. Molecular medicine reports 14 26934949
2007 Apoptosis related protein 3, an ATRA-upregulated membrane protein arrests the cell cycle at G1/S phase by decreasing the expression of cyclin D1. Biochemical and biophysical research communications 12 17524364
2023 Role of APR3 in cancer: apoptosis, autophagy, oxidative stress, and cancer therapy. Apoptosis : an international journal on programmed cell death 10 37634193
2024 Systematic Druggable Genome-Wide Mendelian Randomization Identifies Therapeutic Targets for Functional Outcome After Ischemic Stroke. Journal of the American Heart Association 9 39119979
2015 Apoptosis related protein 3 is a lysosomal membrane protein. Biochemical and biophysical research communications 9 25839652
2012 Increased expression of apoptosis-related protein 3 is highly associated with tumorigenesis and progression of cervical squamous cell carcinoma. Human pathology 9 23036366
2020 An electrochemically reversible lattice with redox active A-sites of double perovskite oxide nanosheets to reinforce oxygen electrocatalysis. Chemical science 8 34094282
2018 APR3 modulates oxidative stress and mitochondrial function in ARPE-19 cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 7 29792731
2023 Illumina RNA and SMRT Sequencing Reveals the Mechanism of Uptake and Transformation of Selenium Nanoparticles in Soybean Seedlings. Plants (Basel, Switzerland) 4 36840137
2019 Interaction of Nel-like molecule 1 with apoptosis related protein 3 with its influence on human dental pulp cells proliferation and differentiation into odontoblasts. Biochemical and biophysical research communications 4 31416616
2023 Functional characterization of all-trans retinoic acid-induced differentiation factor (ATRAID). FEBS open bio 3 37530719
2022 A Mathematical Model of In Vitro Cellular Uptake of Zoledronic Acid and Isopentenyl Pyrophosphate Accumulation. Pharmaceutics 3 35745834
2001 [Anti-proteinase 3 antibodies in diffuse systemic sclerosis (SSc) with normotensive renal impairment: is it suggestive for an overlapping between SSc and idiopathic vasculitis? ]. Reumatismo 3 12461576
2007 [Comparison of the antigenic spectrum A1, A2, and Ax erythrocytes: inhibition of mab with glucoconjugates of lipid and protein nature with different isoelectric properties]. Klinicheskaia laboratornaia diagnostika 2 18225514
2025 Elucidating Cellular Senescence-related Genes in Benign Prostatic Hyperplasia Through Mendelian Randomization and Single-cell RNA Sequencing. The journals of gerontology. Series A, Biological sciences and medical sciences 1 40269514
2006 [Study of the nature of A1- and A2-antigenic differences with use of monoclonal antibodies: a role of glycoprotein and glycolipid epitopes in their formation]. Klinicheskaia laboratornaia diagnostika 1 17144537
2026 Identification of common transcriptional responses to salinity of two halophytes: Bruguiera gymnorrhiza and Populus euphratica. Scientific reports 0 41991566
2026 Cross-ancestry analysis of gestational diabetes mellitus identifies novel loci, drug targets and biological pathways. Frontiers in endocrinology 0 42109742
2025 A feed-forward loop between Toll/NF-κB and Rac1 promotes epithelial to mesenchymal transition of Ras-oncogenic hindgut enterocytes in Drosophila. Biology open 0 40476337
2025 pQTL Mendelian randomization analysis combined with single-cell sequencing to identify biomarkers and drug targets for bladder cancer. Molecular and clinical oncology 0 41158706
2025 Discovering Potential Drug Targets for Irritable Bowel Syndrome Through Genetic Insights: A Mendelian Randomization and Colocalization Study. Gastroenterology research and practice 0 41210213
2025 Identification of novel therapeutic targets for liver fibrosis, cirrhosis, and hepatocellular carcinoma via dual-omics analysis and preliminary exploration of regulatory mechanisms. Clinical and experimental hepatology 0 42021999
2008 [The substantination of isotypical differentiation in AB0 system against nonagglutinogenic acid glycotopes of lipid origin]. Vestnik Rossiiskoi akademii meditsinskikh nauk 0 18494112
2008 [Influence of pH values on the agglutinating capacity of anti-A-monoclonal antibodies and their inhibition of A-glucoconjugates of the lipid and protein nature with various isoelectric properties]. Klinicheskaia laboratornaia diagnostika 0 18807511
2004 [Antibodies to proteinase-3 and myeloperoxidase in systemic vasculitis]. Terapevticheskii arkhiv 0 15230127
2002 [Antineutrophil cytoplasmic antibodies in patients with diffuse diseases of connective tissue]. Terapevticheskii arkhiv 0 12087904
1979 [Proteolytic activity of blood plasma and hemolysed blood in dogs after acute chlorophos poisoning]. Polskie archiwum weterynaryjne 0 400184

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