Affinage

REEP1

Receptor expression-enhancing protein 1 · UniProt Q9H902

Length
201 aa
Mass
22.3 kDa
Annotated
2026-06-10
39 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

REEP1 is a neuron-enriched, membrane curvature-inducing protein of the DP1/Yop1p family that shapes the tubular endoplasmic reticulum and governs ER contacts with the cytoskeleton and with mitochondria (PMID:20200447, PMID:24051375). Through hydrophobic hairpin domains it assembles into complexes with the ER-shaping machinery atlastin-1 and spastin, while its C-terminal cytoplasmic region binds microtubules directly to align the ER along the cytoskeleton; loss of this C-terminal region disrupts the ER network (PMID:20200447). REEP1 also resides at the ER–mitochondria interface, where it carries distinct ER- and mitochondria-targeting subdomains and promotes ER–mitochondria contact formation (PMID:26201691), and it couples ER morphogenesis to lipid droplet homeostasis through interaction with seipin (BSCL2) (PMID:27638887). At mitochondria, REEP1 interacts with the phosphatase PGAM5 to keep DRP1-serine 637 dephosphorylated and thereby permit mitochondrial fission, and it associates with NDUFA4 to preserve complex IV integrity (PMID:28007911, PMID:36520405). Proper N-terminal targeting is required for ER residence, and disease variants that abolish it redirect REEP1 to lipid droplets or mitochondria (PMID:24478229, PMID:28007911). Loss of REEP1 reduces peripheral ER complexity in motor neurons, triggers ER stress, and causes progressive axonal degeneration; REEP1 mutations cause the hereditary spastic paraplegia SPG31 (PMID:16826527, PMID:24051375, PMID:32878877). A conserved membrane-shaping function supports selective autophagy: the fission yeast ortholog is essential for autophagosomal enclosure of ER-phagy cargos via C-terminal amphipathic helices, a function human REEP1-4 can substitute for (PMID:37939137).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 Low

    Establishing REEP1 as the SPG31 disease gene and assigning an initial subcellular location framed the first hypotheses about where it acts.

    Evidence Subcellular fractionation and localization in transfected cells in the gene-identification study

    PMID:16826527

    Open questions at the time
    • Single localization method later superseded by ER assignment
    • No mechanism linking localization to disease
    • Mitochondrial-only assignment not reconciled with ER residence
  2. 2010 High

    Placing REEP1 in the DP1/Yop1p family and showing it complexes with atlastin-1 and spastin and binds microtubules defined its core function as a tubular ER-shaping and ER–cytoskeleton-coupling protein.

    Evidence Co-IP in COS7, domain-deletion mutagenesis, in vitro ER network formation, and neuronal colocalization

    PMID:20200447

    Open questions at the time
    • Stoichiometry and architecture of the REEP1–atlastin–spastin complex unresolved
    • Microtubule-binding motif within the C-terminus not mapped at residue level
  3. 2013 High

    A knockout mouse connected loss of REEP1 to reduced peripheral ER complexity in motor neurons, tying neuronal ER architecture to long-term axon survival.

    Evidence Reep1 exon-2 deletion mice with EM ultrastructure and gait analysis

    PMID:24051375

    Open questions at the time
    • Causal chain from ER morphology to axon degeneration not delineated
    • Cell-autonomous vs non-autonomous contribution unclear
  4. 2014 Medium

    Mapping an N-terminal ER-targeting requirement and a synergistic effect on lipid droplet size with atlastins clarified how missense variants mislocalize REEP1 and connected it to lipid droplet biology.

    Evidence Overexpression of WT/mutant constructs, immunofluorescence, lipid droplet sizing, N-terminal deletion/tagging

    PMID:24478229

    Open questions at the time
    • Targeting signal not defined at sequence level
    • Mechanism of lipid droplet size synergy with atlastins unknown
  5. 2014 Medium

    A Drosophila model revealed that REEP1 confers resistance to ER stress and suppresses Tau aggregation, extending its relevance beyond ER shaping to proteostasis.

    Evidence Drosophila RNAi/overexpression, Tau solubility biochemistry, cross-species rescue

    PMID:25096240

    Open questions at the time
    • Molecular link between REEP1 and Tau aggregation not defined
    • Relevance to mammalian neurons not established here
  6. 2012 Medium

    Comparing an HSP missense variant against a dHMN truncation variant showed divergent mislocalization and atlastin-1 recruitment, indicating distinct pathogenic mechanisms across REEP1-linked disorders.

    Evidence Overexpression localization, atlastin-1 co-recruitment, minigene splice assay

    PMID:22703882

    Open questions at the time
    • Endogenous-level validation lacking
    • Functional consequence of altered atlastin-1 recruitment unmeasured
  7. 2015 High

    Demonstrating REEP1 subdomains for both ER and mitochondrial localization and a measurable role in ER–mitochondria contact formation established it as a membrane contact-site organizer disrupted by disease mutations.

    Evidence Fractionation, split-RLuc8 contact-site assay, neuronal knockdown growth/degeneration assays

    PMID:26201691

    Open questions at the time
    • Tethering partners at the contact site not identified
    • Quantitative contribution to organelle communication unknown
  8. 2016 High

    Identifying seipin as a REEP1 binding partner and documenting lipoatrophy and lipid droplet defects in null mice linked REEP1-dependent ER morphogenesis to lipid droplet regulation.

    Evidence Reep1-null mice, lipid droplet staining, reciprocal Co-IP with seipin, MRI

    PMID:27638887

    Open questions at the time
    • Functional consequence of REEP1–seipin interaction on droplet biogenesis not mechanistically resolved
    • Tissue specificity of lipoatrophy phenotype unexplained
  9. 2017 Medium

    Showing that impaired REEP1–PGAM5 interaction causes DRP1-S637 hyperphosphorylation and excessively tubular mitochondria, reversible by reducing that phosphorylation, defined a mitochondrial fission control pathway in SPG31.

    Evidence SPG31 patient fibroblasts, phospho-DRP1 assays, REEP1–PGAM5 interaction, neuronal mitochondrial transport imaging, rescue

    PMID:28007911

    Open questions at the time
    • Direct biochemical reconstitution of REEP1–PGAM5–DRP1 axis lacking
    • Whether mutant mitochondrial mislocalization is cause or consequence not resolved
  10. 2017 Medium

    A nonstop variant producing a C-terminally extended, self-aggregating protein revealed a toxic gain-of-function mechanism distinct from HSP loss-of-function.

    Evidence Expression of nonstop variant, aggregation assays with REEP1 and reporter fusions, mRNA/protein analysis

    PMID:29124833

    Open questions at the time
    • In vivo relevance of the aggregation phenotype not tested
    • Cellular toxicity pathway downstream of aggregation undefined
  11. 2020 Medium

    Demonstrating elevated ER stress markers in REEP1-null mice and rescue by salubrinal placed ER stress downstream of REEP1 deficiency as a tractable degeneration mechanism.

    Evidence REEP1 KO mice, ER stress marker quantification, salubrinal treatment, NMJ and motor readouts

    PMID:32878877

    Open questions at the time
    • Molecular trigger linking ER shape loss to the unfolded protein response unclear
    • Durability and translational relevance of pharmacological rescue untested
  12. 2022 Medium

    Identifying a REEP1–NDUFA4 association needed for complex IV integrity, and showing REEP1 overexpression is neuroprotective in SOD1G93A mice, extended REEP1's mitochondrial role to oxidative phosphorylation and broader motor neuron disease.

    Evidence Co-IP with NDUFA4, complex IV activity assays, AAV REEP1 overexpression in SOD1G93A mice

    PMID:36520405

    Open questions at the time
    • Mechanism by which REEP1 supports complex IV assembly/stability unknown
    • Whether benefit is via complex IV or general mitochondrial support unresolved
  13. 2023 High

    Cross-species work showed the REEP1 ortholog is essential for autophagosomal enclosure of ER-phagy cargos via C-terminal amphipathic helices, with human REEP1-4 rescuing the yeast defect, establishing a conserved membrane-shaping role in selective autophagy.

    Evidence S. pombe imaging screen, deletion mutants, domain mutagenesis, human REEP1-4 complementation

    PMID:37939137

    Open questions at the time
    • Direct demonstration of ER-phagy enclosure function for human REEP1 in mammalian neurons lacking
    • How membrane shaping mechanistically drives enclosure not resolved
  14. 2024 Low

    Linking REEP1 to MAM formation and an NDPK-D interaction that limits cardiolipin externalization tied REEP1 to autophagosome biogenesis in a neurodegeneration model.

    Evidence ER-mitochondria co-localization, cardiolipin probe in MAM fractions, REEP1–NDPK-D interaction, autophagosome staining, A53T-αSyn mice

    PMID:39178680

    Open questions at the time
    • REEP1–NDPK-D binding supported only by co-localization, no rigorous binding assay
    • Single pharmacological-intervention study, not independently confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How REEP1's single membrane-shaping activity is mechanistically partitioned across its multiple contexts—tubular ER, ER–mitochondria contacts, lipid droplet regulation, mitochondrial fission/complex IV, and selective autophagy—and which functions are most relevant to SPG31 axonal degeneration remains unresolved.
  • No structural model integrating curvature induction with partner binding
  • Relative contribution of ER vs mitochondrial defects to motor neuron loss undefined
  • Endogenous interactome at neuronal contact sites not comprehensively mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0008092 cytoskeletal protein binding 1 GO:0008289 lipid binding 1
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005739 mitochondrion 3 GO:0005811 lipid droplet 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-8953897 Cellular responses to stimuli 1 R-HSA-9612973 Autophagy 1
Partners
ATL1BSCL2NDUFA4NME4PGAM5SPAST

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 REEP1 is structurally related to the DP1/Yop1p family of ER-shaping proteins and localizes to the tubular ER in neurons. REEP1 forms protein complexes with atlastin-1 and spastin within the tubular ER, interactions requiring hydrophobic hairpin domains in each protein. REEP1 also binds microtubules directly and promotes ER alignment along the microtubule cytoskeleton. A SPG31 mutant REEP1 lacking the C-terminal cytoplasmic region failed to interact with microtubules and disrupted the ER network. REEP proteins were required for ER network formation in vitro. Co-immunoprecipitation in COS7 cells, overexpression/domain-deletion analysis, in vitro ER network formation assay, immunofluorescence colocalization in rat cortical neurons The Journal of clinical investigation High 20200447
2006 REEP1 was initially reported to localize to mitochondria based on cellular fractionation/localization experiments in the study identifying it as the SPG31 disease gene. Subcellular fractionation and localization assays in transfected cells American journal of human genetics Low 16826527
2013 REEP1 is a neuron-specific, membrane-binding, and membrane curvature-inducing protein residing in the ER. In REEP1-deficient mice (homozygous exon 2 deletion), cortical motor neurons showed reduced complexity of the peripheral ER by ultrastructural analysis, connecting proper neuronal ER architecture to long-term axon survival. Mouse knockout model (heterozygous and homozygous exon 2 deletion), electron microscopy ultrastructural analysis, behavioral gait analysis The Journal of clinical investigation High 24051375
2015 REEP1 is present at the ER-mitochondria interface, containing subdomains for both mitochondrial and ER localization. REEP1 facilitates ER-mitochondria interactions (measured by split-RLuc8 assay), and disease-associated REEP1 mutations diminish this function. Knockdown of Reep1 and expression of pathological mutations caused neuritic growth defects and degeneration in mouse cortical neurons. Cellular imaging (immunofluorescence/confocal), biochemical fractionation, novel split-RLuc8 bioluminescence complementation assay for ER-mitochondria contacts, neuritic growth/degeneration assays in mouse cortical culture Annals of neurology High 26201691
2016 REEP1 is involved in lipid droplet biology: Reep1-null mice show partial lipoatrophy, and Reep1-/- embryonic fibroblasts and cortical neurons show lipid droplet abnormalities. REEP1 co-immunoprecipitates with seipin (BSCL2) in cells, linking ER morphogenesis to lipid droplet regulation. Reep1 knockout mouse (null allele), lipid droplet staining in fibroblasts and neurons, co-immunoprecipitation of REEP1 with seipin, MRI of mice Human molecular genetics High 27638887
2014 The N-terminus of REEP1 is necessary for proper targeting to and/or retention in the ER. HSP-associated missense variants at the N-terminus abolish ER targeting and cause accumulation at lipid droplets. Co-overexpression of REEP1 with atlastins increases lipid droplet size synergistically, whereas REEP1 alone does not. Overexpression of wild-type and mutant REEP1 constructs in cell lines, immunofluorescence localization, lipid droplet size measurement, N-terminal deletion/tagging experiments Human mutation Medium 24478229
2012 A dHMN-associated internally shortened REEP1 variant (p.102_139del) shows a subcellular localization defect distinct from the HSP-associated missense mutation (p.Ala20Glu). The p.102_139del variant also recruits atlastin-1 (a REEP1 binding partner) to the altered sites of localization, whereas p.Ala20Glu does not, suggesting distinct pathogenic mechanisms for HSP vs. dHMN. Exogenous overexpression in cell lines, immunofluorescence localization, minigene splice assay confirming mRNA consequence American journal of human genetics Medium 22703882
2017 In SPG31 patient fibroblasts, mitochondrial morphology is highly tubular due to hyperphosphorylation of DRP1 at serine 637, which inhibits mitochondrial fission. This hyperphosphorylation is caused by impaired interaction between REEP1 and the mitochondrial phosphatase PGAM5. Genetic or pharmacological reduction of DRP1-S637 phosphorylation restores mitochondrial morphology. Pathological REEP1 mutations expressed in neurons target REEP1 to mitochondria and sequester mitochondria to the perinuclear region, impairing axonal mitochondrial transport. Primary fibroblasts from SPG31 patients, immunofluorescence/confocal mitochondrial morphology analysis, phospho-DRP1 biochemical assays, REEP1-PGAM5 interaction assay, primary neuronal culture with mutant REEP1 overexpression and mitochondrial transport imaging Human molecular genetics Medium 28007911
2017 A nonstop variant in REEP1 produces a C-terminally extended protein whose extension triggers self-aggregation of REEP1 and of reporter proteins, demonstrating a toxic gain-of-function mechanism distinct from the loss-of-function seen in HSP. This aggregation-prone behavior maps to a 3'UTR-encoded cryptic amyloidogenic element. Expression of nonstop variant protein in cells, aggregation assays with REEP1 and reporter fusions, mRNA/protein analysis Human mutation Medium 29124833
2014 In a Drosophila model, downregulation of the REEP1 homolog enhanced Tau toxicity and increased formation of insoluble Tau aggregates, while overexpression of either Drosophila or human REEP1 reversed these phenotypes and promoted neuronal resistance to ER stress, identifying a role for REEP1 in preventing Tau aggregation and in ER stress resistance. Drosophila RNAi screen, Tau toxicity assays, Tau solubility/aggregation biochemistry, REEP1 overexpression rescue experiments in fly model Human molecular genetics Medium 25096240
2022 REEP1 associates with NDUFA4 and plays an important role in preserving the integrity of mitochondrial complex IV. Forced REEP1 expression in the spinal cord of SOD1G93A mice extended lifespan, decelerated symptom progression, improved motor performance, and alleviated neuromuscular synaptic loss and motor neuron loss through augmentation of mitochondrial function. Co-immunoprecipitation of REEP1 with NDUFA4, OXPHOS complex IV activity assays, in vivo AAV-mediated REEP1 overexpression in SOD1G93A mice with behavioral and histological readouts Neuroscience bulletin Medium 36520405
2023 The fission yeast ortholog of human REEP1-4 (Yep1/Hva22/Rop1) is essential for autophagosomal enclosure of ER-phagy and nucleophagy cargos but not bulk autophagy. This function relies on Yep1's ability to self-interact and shape membranes, requiring its C-terminal amphipathic helices. Human REEP1-4 can functionally substitute for Yep1 in ER-phagy, confirming functional conservation. Imaging-based screen in S. pombe, yeast genetics (deletion mutants), complementation assays with human REEP1-4, domain mutagenesis (amphipathic helix deletion), fluorescence microscopy of autophagy intermediates PLoS biology High 37939137
2024 REEP1 enhances MAM (mitochondria-associated ER membrane) formation and interacts with NDPK-D at mitochondria; increased REEP1 levels at mitochondria reduce cardiolipin (CL) externalization via the REEP1-NDPK-D interaction, thereby promoting autophagosome biogenesis. Fluorescent staining for ER-mitochondria co-localization, cardiolipin probe assay in MAM fractions, co-localization/interaction assays of REEP1 with NDPK-D, monodansylcadaverine staining for autophagosomes in SH-SY5Y cells, in vivo A53T-αSyn mouse model with behavioral tests Phytomedicine Low 39178680
2020 REEP1-null mice exhibit increased ER stress markers alongside progressive motor deficits and axonal degeneration; treatment with salubrinal (an ER stress inhibitor) increased nerve-muscle connections and enhanced motor functions, implicating ER stress as a downstream mechanism of REEP1 deficiency. REEP1 knockout mouse model, ER stress marker quantification, salubrinal pharmacological treatment, neuromuscular junction innervation analysis, behavioral motor testing Biology open Medium 32878877

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network. The Journal of clinical investigation 318 20200447
2006 Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. American journal of human genetics 190 16826527
2008 REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain : a journal of neurology 146 18321925
2015 Hereditary spastic paraplegia-linked REEP1 modulates endoplasmic reticulum/mitochondria contacts. Annals of neurology 85 26201691
2016 Reep1 null mice reveal a converging role for hereditary spastic paraplegia proteins in lipid droplet regulation. Human molecular genetics 82 27638887
2011 REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction. Human mutation 79 21618648
2012 Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V. American journal of human genetics 77 22703882
2013 A spastic paraplegia mouse model reveals REEP1-dependent ER shaping. The Journal of clinical investigation 76 24051375
2014 Functional mutation analysis provides evidence for a role of REEP1 in lipid droplet biology. Human mutation 51 24478229
2011 Mutation screening of spastin, atlastin, and REEP1 in hereditary spastic paraplegia. Clinical genetics 45 20718791
2008 New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP). Neurogenetics 38 19034539
2017 Mitochondrial morphology and cellular distribution are altered in SPG31 patients and are linked to DRP1 hyperphosphorylation. Human molecular genetics 35 28007911
2008 Autosomal dominant hereditary spastic paraplegia: novel mutations in the REEP1 gene (SPG31). BMC medical genetics 35 18644145
2013 REEP1 and REEP2 proteins are preferentially expressed in neuronal and neuronal-like exocytotic tissues. Brain research 33 24355597
2015 Molecular spectrum of the SPAST, ATL1 and REEP1 gene mutations associated with the most common hereditary spastic paraplegias in a group of Polish patients. Journal of the neurological sciences 25 26671083
2015 Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy. Neurology. Genetics 20 27066569
2014 Mutation analysis of SPAST, ATL1, and REEP1 in Korean Patients with Hereditary Spastic Paraplegia. Journal of clinical neurology (Seoul, Korea) 20 25045380
2017 A nonstop variant in REEP1 causes peripheral neuropathy by unmasking a 3'UTR-encoded, aggregation-inducing motif. Human mutation 17 29124833
2012 ATL1 and REEP1 mutations in hereditary and sporadic upper motor neuron syndromes. Journal of neurology 15 23108492
2023 The ortholog of human REEP1-4 is required for autophagosomal enclosure of ER-phagy/nucleophagy cargos in fission yeast. PLoS biology 13 37939137
2019 Peripheral neuropathy in hereditary spastic paraplegia caused by REEP1 variants. Journal of neurology 13 30637453
2014 Functional screening in Drosophila reveals the conserved role of REEP1 in promoting stress resistance and preventing the formation of Tau aggregates. Human molecular genetics 13 25096240
2020 Inhibition of ER stress improves progressive motor deficits in a REEP1-null mouse model of hereditary spastic paraplegia. Biology open 12 32878877
2024 Phillyrin promotes autophagosome formation in A53T-αSyn-induced Parkinson's disease model via modulation of REEP1. Phytomedicine : international journal of phytotherapy and phytopharmacology 11 39178680
2017 Spastic paraplegia type 31: A novel REEP1 splice site donor variant and expansion of the phenotype variability. Parkinsonism & related disorders 11 29107646
2009 Clinical and genetic study of a novel mutation in the REEP1 gene. Synapse (New York, N.Y.) 11 19072839
2022 REEP1 Preserves Motor Function in SOD1G93A Mice by Improving Mitochondrial Function via Interaction with NDUFA4. Neuroscience bulletin 10 36520405
2020 A complete overview of REEP1: old and new insights on its role in hereditary spastic paraplegia and neurodegeneration. Reviews in the neurosciences 10 31913854
2014 A recurrent deletion syndrome at chromosome bands 2p11.2-2p12 flanked by segmental duplications at the breakpoints and including REEP1. European journal of human genetics : EJHG 8 24986827
2023 Converging Role for REEP1/SPG31 in Oxidative Stress. International journal of molecular sciences 7 36834939
2017 Hereditary spastic paraplegia due to a novel mutation of the REEP1 gene: Case report and literature review. Medicine 7 28099355
2020 Screening for REEP1 Mutations in 31 Chinese Hereditary Spastic Paraplegia Families. Frontiers in neurology 5 32655478
2024 Generation of a human induced pluripotent stem cell line (FSMi001-A) from fibroblasts of a patient carrying heterozygous mutation in the REEP1 gene. Stem cell research 3 38889632
2022 A clinical and genetic study of SPG31 in Japan. Journal of human genetics 2 35132160
2024 Generation of homozygous and heterozygous REEP1 knockout induced pluripotent stem cell lines by CRISPR/Cas9 gene editing. Stem cell research 1 38479332
2019 [Deletional variant of REEP1 gene in a pedigree affected with spastic paraplegia type 31]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 31055810
2024 Phenotypic variability in a large kindred with spastic paraplegia associated with a novel REEP1 variant. eNeurologicalSci 0 38525447
2023 Double gene mutations of LRSAM1 and REEP1 and a new REEP1 mutation site found in a patient with amyotrophic lateral sclerosis with subjective paresthesia: A case report. Ibrain 0 41018230
2020 A novel REEP1 splicing mutation with broad clinical variability in a family with hereditary spastic paraplegia. Gene 0 32905827

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