Affinage

REEP3

Receptor expression-enhancing protein 3 · UniProt Q6NUK4

Length
255 aa
Mass
29.3 kDa
Annotated
2026-06-10
25 papers in source corpus 7 papers cited in narrative 7 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

REEP3 is an endoplasmic reticulum membrane protein that, acting redundantly with the closely related REEP4, governs ER organization during mitosis to ensure proper cell division and nuclear envelope architecture (PMID:23911198). It links the ER to microtubules through a short, positively charged sequence between its two hydrophobic domains, an interaction required to clear ER membranes from metaphase chromosomes; loss of REEP3/4 causes ER accumulation on chromatin, division defects, and proliferation of intranuclear membranes derived from the nuclear envelope (PMID:23911198). Separately from this clearance function, REEP3 shapes metaphase ER by promoting high-curvature tubulation via its reticulon homology domain, with its C-terminus mediating regulation of the protein (PMID:30995177). Beyond mitotic ER biology, REEP3 negatively regulates hepatic Factor VII (F7) expression, as its silencing in liver cells upregulates F7 mRNA and FVII protein (PMID:30642921). Reported roles in adipogenesis, cortical neuronal fate, and airway stenosis have not been mechanistically resolved in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2007 Low

    Before any function was defined, a position-effect loss of REEP3 expression in an autism patient first nominated REEP3 as a candidate neurodevelopmental gene and noted its homology to a yeast ER/Golgi trafficking regulator.

    Evidence Cytogenetic mapping and RT-PCR of patient lymphoblasts identifying a de novo balanced inversion abolishing REEP3 expression

    PMID:17290275

    Open questions at the time
    • Single patient, expression measurement only
    • No functional rescue or mechanistic link between REEP3 loss and phenotype
    • Molecular function of REEP3 unaddressed
  2. 2013 High

    The core mechanistic role was established by showing REEP3/4 act as microtubule-membrane linkers that clear ER from metaphase chromosomes, settling how the ER is excluded from chromatin during division.

    Evidence Biochemical screen for microtubule-membrane linkers plus siRNA depletion, live-cell imaging, electron microscopy, and domain mutagenesis in HeLa cells

    PMID:23911198

    Open questions at the time
    • Direct microtubule-binding partners and regulators not fully defined
    • Redundancy with REEP4 complicates assignment of REEP3-specific contribution
    • Mechanism of intranuclear membrane proliferation upon depletion not resolved
  3. 2019 High

    Mitotic ER shaping was separated from ER clearance, defining the reticulon homology domain as the driver of high-curvature tubulation distinct from the chromosome-clearance activity.

    Evidence siRNA depletion, electron tomography of ER morphology, and domain deletion/mutation with rescue in cultured cells

    PMID:30995177

    Open questions at the time
    • How C-terminal regulation couples the two activities not detailed
    • Structural basis of RHD-induced curvature not determined
  4. 2019 Medium

    A function outside mitosis emerged: REEP3 negatively regulates hepatic coagulation Factor VII, linking it to control of F7 expression.

    Evidence siRNA silencing of REEP3 in HuH7 liver cells with measurement of F7 mRNA and FVII protein

    PMID:30642921

    Open questions at the time
    • Single cell line and single method
    • Mechanism connecting an ER-shaping protein to F7 transcription unknown
    • No in vivo confirmation
  5. 2025 Low

    Candidate organismal roles in adipogenesis and cortical neuronal composition were probed, extending REEP3 beyond cell-division biology.

    Evidence Overexpression/knockdown in adipocyte differentiation assays; CRISPR/Cas9 disruption in mouse neocortex with cell-fate analysis

    PMID:34790688 PMID:39862915

    Open questions at the time
    • No molecular mechanism or pathway placement for either role
    • Limited mechanistic detail in source reports
    • Relationship to the ER-shaping function untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how REEP3's defined ER-membrane/microtubule activities mechanistically connect to its proposed roles in transcriptional control of F7, adipogenesis, and neuronal fate.
  • No unifying molecular mechanism across contexts
  • REEP3-specific (vs REEP4-redundant) contributions largely undefined
  • No structural model of the protein

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 1 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005635 nuclear envelope 1
Pathway
R-HSA-1640170 Cell Cycle 1 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
REEP4

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 REEP3 and REEP4 function redundantly to clear the endoplasmic reticulum from metaphase chromosomes during mitosis. Depletion of REEP3/4 from HeLa cells causes ER accumulation on metaphase chromosomes, defects in cell division, and proliferation of intranuclear membranes derived from the nuclear envelope. Microtubule binding and mitotic ER clearance depend on a short, positively charged amino acid sequence connecting the two hydrophobic domains of REEP4 (and by inference REEP3). Biochemical screen for microtubule-membrane linkers; siRNA depletion of REEP3/4 in HeLa cells; live-cell imaging; electron microscopy of nuclear envelope architecture Developmental cell High 23911198
2019 REEP3 and REEP4 are major determinants of ER morphology in metaphase cells, promoting high-curvature ER tubulation through their reticulon homology domains (RHDs). This ER-shaping activity is distinct from their function in clearing ER from metaphase chromatin. Related REEP proteins do not contribute to mitotic ER shaping, and the REEP3/4 C-terminus mediates regulation of the proteins. siRNA depletion of REEP3/4 in cultured cells; electron tomography (3View) of ER morphology; domain deletion/mutation analysis; live-cell fluorescence imaging Molecular biology of the cell High 30995177
2007 REEP3 expression is abolished by a chromosomal position effect caused by a de novo balanced paracentric inversion inv(10)(q11.1;q21.3) in a patient with autism, placing REEP3 as a candidate gene whose loss-of-expression may contribute to neurodevelopmental phenotypes. REEP3 is described as a homolog of yeast Yop1p, a regulator of vesicle trafficking between ER and Golgi. Cytogenetic mapping; RT-PCR quantification of REEP3 mRNA expression in patient lymphoblasts; positional cloning European journal of human genetics : EJHG Low 17290275
2019 Silencing of REEP3 in the human liver cell line HuH7 using siRNA upregulated Factor VII (F7) mRNA and FVII protein expression, indicating that REEP3 negatively regulates F7 expression in hepatic cells. siRNA-mediated silencing of REEP3 in HuH7 cells followed by measurement of F7 mRNA and FVII protein expression Blood Medium 30642921
2021 REEP3 was identified as a positive regulator of adipogenesis in an m6A-independent pathway. Rhein treatment altered REEP3 expression, and modulation of REEP3 levels affected adipocyte differentiation. Transcriptome profiling; m6A methylome analysis; REEP3 overexpression/knockdown in adipocyte differentiation assays Frontiers in nutrition Low 34790688
2025 Loss-of-function analysis using CRISPR/Cas9 disruption of Reep3 in mouse cortical cells affected cortical cell fate and the composition of cortical neurons, suggesting a role for REEP3 in generating appropriate cortical neuronal composition. CRISPR/Cas9 loss-of-function in mouse neocortex; cortical cell fate analysis Progress in neuro-psychopharmacology & biological psychiatry Low 39862915
2025 REEP3, along with FAM118A, RCN3, and PCSK7, was found to promote airway stenosis by activating the KRAS→PI3K-AKT pathway, leading to upregulation of fibroblast activation markers. REEP3 expression is transcriptionally regulated by TBX20, and the ILF3-AS1/miR-212-5p axis regulates REEP3 expression. Integration of single-cell and bulk RNA-seq; molecular biology validation assays; pathway activation measurement Functional & integrative genomics Low 41432785

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. American journal of human genetics 358 18940312
2023 Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy. Nature genetics 146 37337107
2013 REEP3/4 ensure endoplasmic reticulum clearance from metaphase chromatin and proper nuclear envelope architecture. Developmental cell 113 23911198
2007 Identification and characterization of the TRIP8 and REEP3 genes on chromosome 10q21.3 as novel candidate genes for autism. European journal of human genetics : EJHG 62 17290275
2017 Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder. Nature communications 50 29042551
2019 A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology. Blood 42 30642921
2019 REEP3 and REEP4 determine the tubular morphology of the endoplasmic reticulum during mitosis. Molecular biology of the cell 37 30995177
2022 5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Diagnostic Biomarkers for Late-Onset Alzheimer's Disease. Journal of Alzheimer's disease : JAD 33 34864677
2019 Genome-wide association study of blood lipids in Indians confirms universality of established variants. Journal of human genetics 29 30911093
2020 CircFAT1 promotes hepatocellular carcinoma progression via miR-30a-5p/REEP3 pathway. Journal of cellular and molecular medicine 28 33179443
2022 The REEP family of proteins: Molecular targets and role in pathophysiology. Pharmacological research 25 36191880
2021 The Phytochemical Rhein Mediates M6A-Independent Suppression of Adipocyte Differentiation. Frontiers in nutrition 18 34790688
2021 Genetic basis of chicken plumage color in artificial population of complex epistasis. Animal genetics 16 34224160
2017 The DNA methylation landscape of CD4+ T cells in oligoarticular juvenile idiopathic arthritis. Journal of autoimmunity 14 28969936
2021 Whole genome sequencing of nearly isogenic WMI and WLI inbred rats identifies genes potentially involved in depression and stress reactivity. Scientific reports 12 34285244
2009 Loss of REEP4 causes paralysis of the Xenopus embryo. The International journal of developmental biology 10 19123125
2023 Expression Quantitative Trait Methylation Analysis Identifies Whole Blood Molecular Footprint in Fetal Alcohol Spectrum Disorder (FASD). International journal of molecular sciences 9 37047575
2021 Identifi cation of the Underlying Genetic Factors of Skin Aging in a Korean Population Study. Journal of cosmetic science 7 35349426
2011 In silico identification of new candidate genes for hereditary congenital facial paresis. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 6 21345367
2023 Multiomics and bioinformatics identify differentially expressed effectors in the brain of Toxoplasma gondii infected masked palm civet. Frontiers in cellular and infection microbiology 5 37818043
2022 Identification of genes contributing to cisplatin resistance in osteosarcoma cells. FEBS open bio 5 36408691
2025 Unveiling migraine subtype heterogeneity and risk loci: integrated genome-wide association study and single-cell transcriptomics discovery. The journal of headache and pain 4 40826382
2025 Deciphering the molecular clock: exploring molecular mechanisms and genetic influences on skin ageing. Biogerontology 2 40751759
2025 Local cortical structure pattern and genetic links in schizophrenia: An MRI and CRISPR/Cas9 study. Progress in neuro-psychopharmacology & biological psychiatry 1 39862915
2025 Integrating single-cell and bulk RNA-Seq to unravel the molecular mechanisms of airway stenosis. Functional & integrative genomics 0 41432785

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