Affinage

REEP1

Receptor expression-enhancing protein 1 · UniProt Q9H902

Length
201 aa
Mass
22.3 kDa
Annotated
2026-04-28
39 papers in source corpus 12 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

REEP1 is a neuron-enriched ER-shaping protein that generates membrane curvature through hydrophobic hairpin domains to build and maintain the tubular ER network, and couples ER tubules to the microtubule cytoskeleton via its C-terminal cytoplasmic region (PMID:20200447, PMID:24051375). It forms complexes with atlastin-1 and spastin through its hairpin domains, cooperates with seipin in lipid droplet regulation, and resides at ER–mitochondria contact sites where it interacts with PGAM5 to regulate DRP1-S637 phosphorylation and mitochondrial fission, and with NDUFA4 to support complex IV integrity (PMID:20200447, PMID:27638887, PMID:26201691, PMID:28007911, PMID:36520405). REEP1 is functionally required for ER-phagy, as demonstrated by conservation of this role from fission yeast to human, dependent on its self-interaction and membrane-shaping activity (PMID:37939137). Loss-of-function mutations in REEP1 cause hereditary spastic paraplegia (SPG31) through haploinsufficiency with ER morphology defects, while certain gain-of-function mutations produce mislocalized or aggregation-prone proteins with distinct neurotoxic effects (PMID:24051375, PMID:29124833, PMID:28007911).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2010 High

    Establishing REEP1 as an ER-shaping protein that cooperates with atlastin-1 and spastin answered how three HSP-linked gene products converge on a shared membrane-remodeling function at the tubular ER.

    Evidence Reciprocal co-IP in COS7 cells, domain mutagenesis, in vitro ER network reconstitution, and neuronal co-localization

    PMID:20200447

    Open questions at the time
    • Stoichiometry and direct binding interfaces between REEP1, atlastin-1, and spastin remain unresolved
    • No structural model of the REEP1 hairpin domains in a lipid bilayer
  2. 2010 High

    Demonstrating that REEP1 binds microtubules through its C-terminal cytoplasmic region and that SPG31 truncation mutants lose this activity explained how ER–cytoskeleton coupling fails in disease.

    Evidence Microtubule binding assay, overexpression of wild-type versus C-terminally truncated REEP1 in COS7 cells

    PMID:20200447

    Open questions at the time
    • Identity of the microtubule-binding motif within the C-terminus is not mapped at residue level
    • Whether REEP1 binds microtubules directly or through adaptors in vivo is unresolved
  3. 2013 High

    A mouse knockout confirmed REEP1 is essential for peripheral ER complexity in cortical motor neurons in vivo, grounding prior in vitro findings in a physiological model of axonal vulnerability.

    Evidence Reep1 exon-2 deletion mouse, ultrastructural EM of neuronal ER, membrane curvature assays

    PMID:24051375

    Open questions at the time
    • Whether ER complexity defects are cell-autonomous or influenced by non-neuronal cells is unknown
    • Behavioral and electrophysiological progression in Reep1-null mice was not fully characterized at this stage
  4. 2014 Medium

    Analysis of distinct REEP1 mutations revealed that an internal deletion mislocalizes REEP1 and recruits atlastin-1, whereas a missense mutant does not, establishing that different pathological mutations drive distinct cellular pathomechanisms.

    Evidence Overexpression of deletion and missense REEP1 mutants in cell lines with atlastin-1 co-localization imaging

    PMID:22703882

    Open questions at the time
    • No reciprocal co-IP was performed to validate the altered interaction
    • Only two mutations were compared; broader allelic series needed
  5. 2014 Medium

    A Drosophila Tau toxicity model showed that REEP1 ortholog depletion enhances protein aggregation and ER stress, while overexpression rescues, linking REEP1 to neuronal proteostasis.

    Evidence RNAi knockdown and overexpression in Drosophila, insoluble aggregate and ER stress assays

    PMID:25096240

    Open questions at the time
    • Whether the anti-aggregation effect is direct or secondary to ER morphology changes is unclear
    • Has not been independently replicated in mammalian Tau models
  6. 2015 High

    Identification of REEP1 at ER–mitochondria contact sites with subdomains targeting each organelle expanded its role beyond ER shaping to inter-organelle communication relevant to axonal maintenance.

    Evidence Split-RLuc8 ER–mitochondria proximity assay, biochemical fractionation, knockdown and mutant expression in mouse cortical neurons

    PMID:26201691

    Open questions at the time
    • The molecular tethering mechanism at the MAM is not defined
    • Functional consequences of disrupted MAM contacts on calcium or lipid transfer were not measured
  7. 2016 High

    Discovery of a REEP1–seipin interaction and lipid droplet abnormalities in Reep1-null cells connected ER shaping to lipid droplet homeostasis.

    Evidence Co-IP in cells, lipid droplet imaging in Reep1-null MEFs and cortical neurons

    PMID:27638887

    Open questions at the time
    • Whether REEP1 acts on lipid droplet budding, growth, or turnover is unresolved
    • Direct versus seipin-mediated mechanism not distinguished
  8. 2017 High

    The REEP1–PGAM5 interaction and its control of DRP1-S637 phosphorylation provided a mechanistic link between ER morphology and mitochondrial fission regulation, explaining hypertubular mitochondria in SPG31 patient cells.

    Evidence Co-IP, phospho-DRP1 immunoblotting, genetic and pharmacological rescue in SPG31 patient fibroblasts

    PMID:28007911

    Open questions at the time
    • Whether REEP1 modulates PGAM5 phosphatase activity directly or through scaffolding is unknown
    • Not tested in motor neurons or in vivo
  9. 2017 Medium

    A nonstop REEP1 variant was shown to produce a C-terminally extended, aggregation-prone protein, establishing a gain-of-function toxicity mechanism distinct from haploinsufficiency.

    Evidence Minigene expression, protein aggregation assay with reporter constructs

    PMID:29124833

    Open questions at the time
    • Single lab finding; aggregation has not been confirmed in patient-derived cells or in vivo
    • Whether the aggregates are toxic through proteostasis disruption or sequestration of partners is unclear
  10. 2022 Medium

    Association of REEP1 with NDUFA4 and enhancement of complex IV activity upon REEP1 overexpression in an ALS mouse model extended its mitochondrial role to respiratory chain integrity and neuroprotection.

    Evidence Co-IP of REEP1 with NDUFA4, viral overexpression in SOD1G93A mouse spinal cord, complex IV activity assay

    PMID:36520405

    Open questions at the time
    • Single lab; the REEP1–NDUFA4 interaction awaits reciprocal validation
    • Whether the neuroprotective effect is mediated through complex IV or additional pathways is unresolved
  11. 2023 High

    Demonstration that REEP1 ortholog Yep1 is essential for ER-phagy in fission yeast—and that human REEP1 complements this function—established ER-phagy as a conserved REEP1-dependent process requiring self-interaction and membrane-shaping activity.

    Evidence Imaging-based screen in S. pombe, domain deletion mutant analysis, human REEP1-4 complementation

    PMID:37939137

    Open questions at the time
    • The mammalian ER-phagy receptor(s) that cooperate with REEP1 are not identified
    • Whether REEP1 ER-phagy function is relevant to HSP pathogenesis has not been tested
  12. 2024 Medium

    REEP1 at MAM was linked to NDPK-D interaction, cardiolipin externalization control, and autophagosome biogenesis, providing a MAM-localized mechanism connecting REEP1 to autophagy signaling.

    Evidence Co-IP of REEP1 with NDPK-D, cardiolipin probe assay, autophagosome staining in SH-SY5Y cells

    PMID:39178680

    Open questions at the time
    • Single lab; NDPK-D interaction not validated by reciprocal approach
    • Whether cardiolipin externalization changes are a direct or secondary effect of REEP1 is unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how REEP1's multiple functions—ER shaping, microtubule coupling, MAM tethering, mitochondrial fission regulation, lipid droplet homeostasis, and ER-phagy—are coordinated in motor neurons and which deficit is the primary driver of axonal degeneration in SPG31.
  • No high-resolution structure of REEP1 in a membrane context exists
  • Relative contributions of ER-phagy versus ER morphology versus mitochondrial fission defects to HSP pathogenesis are undefined
  • Cell-type-specific interactome of REEP1 in motor neurons has not been systematically mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0008289 lipid binding 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005739 mitochondrion 4 GO:0005783 endoplasmic reticulum 4 GO:0005811 lipid droplet 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-1643685 Disease 2 R-HSA-9612973 Autophagy 2
Partners
ATL1BSCL2DRP1NDUFA4NME4PGAM5SPAST

Evidence

Reading pass · 15 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, where it forms protein complexes with atlastin-1 and spastin via hydrophobic hairpin domains in each protein. Co-immunoprecipitation in COS7 cells, co-localization in cultured rat cerebral cortical neurons, domain mutagenesis The Journal of clinical investigation High 20200447
2010 REEP1 binds microtubules and promotes ER alignment along the microtubule cytoskeleton; a SPG31 mutant REEP1 lacking the C-terminal cytoplasmic region lost microtubule binding and disrupted the ER network. Overexpression and mutant analysis in COS7 cells, in vitro ER network formation assay, microtubule binding assay The Journal of clinical investigation High 20200447
2010 REEP proteins are required for ER network formation in vitro, establishing a direct role in tubular ER shaping. In vitro ER network formation assay with REEP protein depletion/addition The Journal of clinical investigation High 20200447
2013 REEP1 is a neuron-specific, membrane-binding, and membrane curvature-inducing protein that resides in the ER; REEP1-deficient cortical motor neurons show reduced complexity of the peripheral ER by ultrastructural analysis. Mouse knockout model (heterozygous and homozygous Reep1 exon 2 deletion), ultrastructural EM analysis of neuronal ER, membrane curvature assays The Journal of clinical investigation High 24051375
2015 REEP1 is present at the ER-mitochondria interface, contains subdomains for both mitochondrial and ER localization, and facilitates ER-mitochondria interactions; disease-associated mutations diminish this function and cause neuritic growth defects and degeneration. Cellular imaging and biochemical fractionation, split-RLuc8 assay for ER-mitochondria proximity, knockdown and mutant expression in mouse cortical neurons Annals of neurology High 26201691
2016 REEP1 co-immunoprecipitates with seipin in cells, and Reep1-null mouse embryonic fibroblasts and cortical neurons show lipid droplet abnormalities, linking REEP1 to lipid droplet regulation. Co-immunoprecipitation, Reep1 null mouse model, lipid droplet imaging in fibroblasts and neurons Human molecular genetics High 27638887
2014 The N-terminus of REEP1 is necessary for proper ER targeting; HSP-associated N-terminal missense variants abolish ER targeting and cause accumulation at lipid droplets. Co-overexpression of REEP1 with atlastins increases lipid droplet size synergistically. Mutant and deletion overexpression in cell lines, fluorescence microscopy, lipid droplet size measurement Human mutation Medium 24478229
2017 REEP1 interacts with mitochondrial phosphatase PGAM5; impaired REEP1-PGAM5 interaction in SPG31 patient fibroblasts leads to DRP1 hyperphosphorylation at Ser637, inhibiting mitochondrial fission and causing highly tubular mitochondrial morphology. Primary patient fibroblasts, co-immunoprecipitation, phospho-DRP1 immunoblotting, genetic and pharmacological rescue of DRP1-S637 phosphorylation Human molecular genetics High 28007911
2017 Mutant REEP1 proteins (carrying pathological mutations) localize to mitochondria and sequester mitochondria to the perinuclear region of neurons, impairing mitochondrial transport along the axon. Ectopic expression of pathological mutant REEP1 in primary neuronal cultures, live-cell imaging of mitochondrial distribution Human molecular genetics Medium 28007911
2017 A nonstop variant in REEP1 produces a C-terminally extended protein whose extension triggers self-aggregation of REEP1, representing a toxic gain-of-function mechanism distinct from the loss-of-function mechanism underlying HSP. Minigene and protein expression assays, aggregation assays with REEP1 and reporter constructs Human mutation Medium 29124833
2022 REEP1 associates with NDUFA4 and plays a role in preserving the integrity of mitochondrial complex IV; overexpression of REEP1 in SOD1G93A mice augments mitochondrial function and is neuroprotective. Co-immunoprecipitation of REEP1 with NDUFA4, viral overexpression in SOD1G93A mouse spinal cord, mitochondrial complex IV activity assays Neuroscience bulletin Medium 36520405
2014 Downregulation of the Drosophila REEP1 homolog enhances Tau toxicity and formation of insoluble Tau aggregates, while overexpression of Drosophila or human REEP1 reverses these phenotypes and promotes neuronal resistance to ER stress. RNAi knockdown and overexpression in Drosophila Tau toxicity model, insoluble aggregate assay, ER stress assay Human molecular genetics Medium 25096240
2023 In fission yeast, Yep1 (ortholog of human REEP1-4) is essential for ER-phagy and nucleophagy; its ER-phagy role requires self-interaction, membrane-shaping ability, and C-terminal amphipathic helices. Human REEP1-4 can functionally substitute for Yep1 in ER-phagy. Imaging-based screen in S. pombe, deletion and domain mutant analysis, complementation with human REEP1-4 PLoS biology High 37939137
2024 REEP1 localizes within mitochondria-associated ER membranes (MAM) and its increased presence at MAM/mitochondria enhances interaction with NDPK-D, reducing cardiolipin externalization and supporting autophagosome biogenesis. Fluorescent co-localization, cardiolipin probe assay, Co-immunoprecipitation of REEP1 with NDPK-D, monodansylcadaverine staining for autophagosomes in SH-SY5Y cells Phytomedicine Medium 39178680
2012 An internally deleted REEP1 mutant (p.102_139del) shows a subcellular localization defect and recruits atlastin-1 to the altered localization sites, whereas an HSP missense mutant (p.Ala20Glu) does not, indicating distinct pathomechanisms for different REEP1 mutations. Overexpression of mutant REEP1 in cell lines, co-localization imaging with atlastin-1 American journal of human genetics Medium 22703882

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 317 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 81 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 44 20718791
2008 New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP). Neurogenetics 38 19034539
2008 Autosomal dominant hereditary spastic paraplegia: novel mutations in the REEP1 gene (SPG31). BMC medical genetics 35 18644145
2017 Mitochondrial morphology and cellular distribution are altered in SPG31 patients and are linked to DRP1 hyperphosphorylation. Human molecular genetics 33 28007911
2013 REEP1 and REEP2 proteins are preferentially expressed in neuronal and neuronal-like exocytotic tissues. Brain research 32 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 24 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 16 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
2009 Clinical and genetic study of a novel mutation in the REEP1 gene. Synapse (New York, N.Y.) 11 19072839
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
2017 Spastic paraplegia type 31: A novel REEP1 splice site donor variant and expansion of the phenotype variability. Parkinsonism & related disorders 10 29107646
2022 REEP1 Preserves Motor Function in SOD1G93A Mice by Improving Mitochondrial Function via Interaction with NDUFA4. Neuroscience bulletin 9 36520405
2024 Phillyrin promotes autophagosome formation in A53T-αSyn-induced Parkinson's disease model via modulation of REEP1. Phytomedicine : international journal of phytotherapy and phytopharmacology 8 39178680
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
2017 Hereditary spastic paraplegia due to a novel mutation of the REEP1 gene: Case report and literature review. Medicine 7 28099355
2023 Converging Role for REEP1/SPG31 in Oxidative Stress. International journal of molecular sciences 6 36834939
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