Affinage

REEP6

Receptor expression-enhancing protein 6 · UniProt Q96HR9

Length
211 aa
Mass
23.4 kDa
Annotated
2026-06-10
47 papers in source corpus 11 papers cited in narrative 12 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

REEP6 is a transmembrane member of the REEP/Yop1 family of ER-shaping proteins that maintains endoplasmic reticulum and Golgi homeostasis required for the stability and trafficking of membrane signaling enzymes, and is essential for rod photoreceptor survival (PMID:27889058, PMID:28475715). In the retina, expression is driven by the rod transcription factor NRL, which binds an enhancer within Reep6 intron 1 to activate the rod-specific isoform REEP6.1 (PMID:24691551); this isoform carries an exon-5-encoded 27-residue segment whose function cannot be substituted by the canonical REEP6.2 isoform, as exon-5-specific knockout phenocopies full knockout and only REEP6.1 rescues the resulting degeneration (PMID:34104971). Within rods, REEP6 localizes to the inner segment, and its loss expands the distal ER, increases mitochondrial number, triggers ER stress (CHOP, caspase-12), and reduces the guanylate cyclases GC1/GC2 along with other membrane phototransduction proteins, linking REEP6 to cGMP homeostasis and rod viability [PMID:28475715, PMID:bio_10.1101_2025.03.02.641069]. REEP6 participates in vesicular trafficking, residing in a subset of clathrin-coated vesicles and interacting with the t-SNARE Syntaxin3 (PMID:28369466). Beyond the retina, REEP6 facilitates plasma-membrane trafficking of signaling effectors more broadly: it promotes adenylate cyclase 3 (ADCY3) delivery to support β-adrenergic/PKA signaling in adipocytes (PMID:35150731) and supports CXCR1-mediated endocytosis and β-arrestin2 clustering (PMID:27966653). Destabilizing missense and frameshift variants cause progressive rod photoreceptor degeneration in patients and a knock-in mouse model (PMID:27889058).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2005 Medium

    Established the first cellular context for the REEP6 ortholog, placing it in intracellular membrane trafficking before its retinal role was known.

    Evidence In situ hybridization, immunohistochemistry and intracellular localization of the ortholog Dp1l1 in retinal ganglion cells

    PMID:15728532

    Open questions at the time
    • No molecular partners or trafficking step defined
    • Ortholog rather than human REEP6 directly characterized
  2. 2014 High

    Defined how rod-restricted REEP6 expression is achieved and showed it is required for retinal cell survival, connecting a transcriptional program to a functional necessity.

    Evidence ChIP and reporter assays identifying NRL binding in Reep6 intron 1; siRNA/morpholino knockdown in mouse and zebrafish

    PMID:24691551

    Open questions at the time
    • Knockdown phenotype does not reveal the molecular function of REEP6
    • Mechanism of cell death not resolved
  3. 2016 High

    Linked REEP6 to human retinal disease and to the ER-shaping REEP/Yop1 family, showing pathogenic variants destabilize the protein and cause rod degeneration.

    Evidence Patient missense/frameshift variants expressed in cells, human organoid optic cups, and a p.Leu135Pro knock-in mouse with ERG/histology

    PMID:27889058

    Open questions at the time
    • Did not identify the trafficking substrates or partners affected
    • ER-shaping activity inferred from family membership, not directly assayed
  4. 2016 Medium

    Demonstrated a non-retinal trafficking role, implicating REEP6 in receptor endocytosis and downstream signaling.

    Evidence Co-IP, siRNA depletion of REEP5/REEP6, β-arrestin2 clustering, ERK phosphorylation and xenograft assays for CXCR1

    PMID:27966653

    Open questions at the time
    • Single-lab Co-IP without reciprocal structural validation
    • Mechanism by which REEP6 promotes internalization not defined
  5. 2017 High

    Established a concrete molecular mechanism in rods: REEP6 maintains ER/mitochondrial homeostasis and is required for guanylate cyclase stability and cGMP homeostasis.

    Evidence CRISPR knockout mouse with EM, immunofluorescence, ERG, and Western blots for GC1/GC2, CHOP, caspase-12

    PMID:28475715

    Open questions at the time
    • Whether REEP6 directly chaperones GCs or acts indirectly via ER stress unresolved
    • Discrepancy with later reports on degree of GC loss
  6. 2017 Medium

    Placed REEP6 in clathrin-coated vesicle trafficking and identified a SNARE partner, suggesting a vesicular route for delivery of phototransduction proteins.

    Evidence Co-IP with Syntaxin3, clathrin colocalization, and knockout mouse phenotyping

    PMID:28369466

    Open questions at the time
    • Single Co-IP for Syntaxin3 without reciprocal validation
    • Functional consequence of the Syntaxin3 interaction not directly tested
  7. 2021 High

    Showed the rod-specific isoform REEP6.1 carries the essential activity, defining isoform specialization as functionally non-redundant.

    Evidence Exon-5-specific knockout mouse and AAV rescue with REEP6.1 versus REEP6.2

    PMID:34104971

    Open questions at the time
    • Molecular property conferred by the exon-5 segment not defined
    • Why REEP6.2 cannot substitute remains mechanistically unexplained
  8. 2022 High

    Generalized REEP6's trafficking role to a second effector and tissue, showing it delivers ADCY3 to the plasma membrane for β-adrenergic signaling.

    Evidence Knockout mouse and adipocyte knockdown with plasma membrane fractionation for ADCY3 and metabolic/PKA readouts

    PMID:35150731

    Open questions at the time
    • Direct physical interaction between REEP6 and ADCY3 not shown
    • Whether the same mechanism operates in rods for GCs not established
  9. 2022 Medium

    Identified an upstream post-transcriptional regulator of REEP6 in a neuronal pain context, broadening its regulatory landscape.

    Evidence miR-672-5p luciferase reporter targeting the REEP6 3'UTR plus in vivo agomir/antagomir and electrophysiology

    PMID:36064821

    Open questions at the time
    • Mechanistic role of REEP6 in neuronal excitability not defined
    • Relevance to retinal/adipocyte functions unclear
  10. 2026 Medium

    Connected an epitranscriptomic mechanism to REEP6 dosage, showing WTAP-mediated m6A in the 3'UTR promotes REEP6 translation and that its loss causes rod degeneration.

    Evidence Conditional Wtap knockout mouse, m6A-seq, Western blot, and AAV rescue with ERG

    PMID:41796262

    Open questions at the time
    • Direct effect on REEP6 separated from co-regulated PDE6B/RDH12 not isolated
    • Single lab, partial rescue only
  11. 2025 Medium

    Independent knockout reframed the ER/Golgi-maintenance model, showing reduced (not absent) guanylate cyclases and broadly reduced phototransduction transcription with inflammation activation.

    Evidence Independent CRISPR knockout mouse, in vitro ER/Golgi marker imaging, RNA-seq and ERG (preprint)

    PMID:bio_10.1101_2025.03.02.641069

    Open questions at the time
    • Preprint, not peer-reviewed
    • Conflicts with prior report on GC absence and PDE6 trafficking
    • Direct cause of transcriptional downregulation unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether REEP6 directly binds the membrane proteins whose trafficking it supports (GCs, ADCY3, rhodopsin/GRK1) or acts indirectly by shaping ER/Golgi and vesicle compartments remains the central open mechanistic question.
  • No structure of REEP6 or its complexes
  • No demonstrated direct cargo interaction
  • ER-shaping activity not biochemically reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9709957 Sensory Perception 2
Partners
CXCR1REEP5STX3

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 REEP6 expression in rod photoreceptors is regulated by the bZIP transcription factor NRL, which binds within Reep6 intron 1 to drive expression of the rod-specific isoform REEP6.1 through an intronic enhancer sequence. Chromatin immunoprecipitation identified NRL binding at this site, and reporter assays in cultured cells and retinal explants confirmed NRL-directed REEP6.1 expression. Chromatin immunoprecipitation (ChIP), reporter assay, retinal explant transfection, 5'-RACE, exon-specific Taqman assay Human molecular genetics High 24691551
2014 Knockdown of Reep6 in mouse and zebrafish resulted in death of retinal cells, establishing a required role for REEP6 in retinal cell survival. siRNA knockdown in mouse retina; morpholino knockdown in zebrafish Human molecular genetics Medium 24691551
2016 REEP6 is a member of the REEP/Yop1 family of ER-shaping proteins and is expressed in the retina as a retina-specific isoform (REEP6.1). Missense variants p.Pro128Leu and p.Leu135Pro and a REEP6.1-specific frameshift mutant expressed in cultured cells destabilize the protein. A knock-in mouse (p.Leu135Pro) shows progressive rod photoreceptor degeneration and dysfunction. Human 3D organoid optic cups; CRISPR-Cas9 knock-in mouse; overexpression in cultured cells; electroretinography; histology American journal of human genetics High 27889058
2017 In rod photoreceptors, REEP6 localizes to the inner segment and outer plexiform layer. REEP6 knockout mice show expansion of the distal ER and increased mitochondria number in rods, severely reduced expression of retinal guanylate cyclases GC1 and GC2 (near-undetectable), and ER stress markers (elevated CHOP and activated caspase-12), implicating REEP6 in maintaining cGMP homeostasis through facilitating the stability/trafficking of guanylate cyclases and ER/mitochondrial homeostasis. Rhodopsin, Rom1, and peripherin/rds trafficking were unaffected. CRISPR/Cas9 knockout mouse; transmission electron microscopy; 3View serial block-face scanning EM; immunofluorescence localization; electroretinography; Western blot for GC1, GC2, CHOP, caspase-12 Human molecular genetics High 28475715
2017 REEP6 is detected in a subset of Clathrin-coated vesicles in rod photoreceptors and interacts with the t-SNARE Syntaxin3. Loss of REEP6 causes aberrant accumulation of vacuole-like structures at the apical inner segment and reduction in selected rod phototransduction proteins. Co-immunoprecipitation; immunofluorescence colocalization with Clathrin; Reep6 knockout mouse; electroretinography Human molecular genetics Medium 28369466
2016 REEP6 interacts with CXCR1 (but not CXCR2) and, together with REEP5, facilitates ligand-stimulated endocytosis of CXCR1 and intracellular clustering of β-arrestin2. Depletion of REEP5/REEP6 impairs receptor internalization and reduces IL-8-stimulated ERK phosphorylation and actin polymerization without affecting CXCR1 plasma membrane expression. Co-immunoprecipitation; siRNA knockdown; overexpression; β-arrestin2 clustering assay; ERK phosphorylation Western blot; in vivo xenograft model Scientific reports Medium 27966653
2021 The retina-specific isoform Reep6.1 (containing exon 5-encoded 27 aa) has rod-specific functions that cannot be substituted by the canonical isoform Reep6.2. Exon-5-specific knockout (Reep6E5/E5) produces rod degeneration comparable to full Reep6 knockout, and overexpression of Reep6.2 fails to rescue this phenotype whereas overexpression of Reep6.1 does rescue it. Isoform-specific knockout mouse (exon 5 deletion); AAV-mediated overexpression rescue experiment; electroretinography; histology Human molecular genetics High 34104971
2022 REEP6 plays a cell-autonomous role in β-adrenergic signal transduction in adipocytes by facilitating the trafficking of adenylate cyclase 3 (ADCY3) to the plasma membrane. REEP6 KO reduces ADCY3 plasma membrane targeting, severely reduces protein kinase A-mediated signaling in brown adipose tissue, and reduces mitochondrial mass. These defects were reproduced in cultured adipocytes, confirming cell autonomy. REEP6 knockout mouse; high-fat diet model; siRNA knockdown in C3H10T1/2 adipocytes and primary adipocytes; indirect calorimetry; confocal and electron microscopy; Western blot; mitochondrial DNA analysis; plasma membrane fractionation for ADCY3 Metabolism: clinical and experimental High 35150731
2022 miR-672-5p directly regulates REEP6 expression in spinal dorsal horn neurons (validated by dual-luciferase reporter assay targeting the REEP6 mRNA 3'UTR). Upregulation of REEP6 in dorsal horn neurons contributes to neuronal hyperexcitability and mechanical allodynia in bortezomib-induced neuropathic pain. miRNA microarray; PCR; dual-luciferase reporter assay; intrathecal injection of miR-672-5p agomir/antagomir; sEPSC recording; REEP6 overexpression/knockdown in vivo Neurochemical research Medium 36064821
2005 The REEP6 ortholog Dp1l1 (TB2-like 1) localizes to the cytoplasm in a punctate pattern in retinal ganglion cells, consistent with a role in intracellular membrane trafficking, as determined by immunohistochemistry and intracellular localization analyses. In situ hybridization; immunohistochemistry; intracellular localization analysis; radiation hybrid mapping Investigative ophthalmology & visual science Medium 15728532
2026 WTAP-mediated m6A methylation facilitates translation of REEP6 (and PDE6B, RDH12) in rod photoreceptors by depositing m6A modifications in the 3'UTR of Reep6 mRNA. Loss of Wtap abolished WTAP-mediated methyltransferase complex stability, reduced m6A levels genome-wide, and caused epigenetic silencing of Reep6 with consequent rod degeneration; AAV-mediated reintroduction of WTAP partially restored REEP6 expression and mitigated degeneration. Conditional Wtap knockout mouse; m6A-seq; Western blot; AAV gene therapy rescue; ERG Science China. Life sciences Medium 41796262
2025 In vitro expression of REEP6 alters ER marker expression and Golgi morphology. In an independent Reep6 knockout mouse, guanylate cyclases are not absent but are reduced ~one-third, rhodopsin and GRK1 are also reduced, PDE6 trafficking is normal (contrasting a prior report), and RNA-seq shows reduced phototransduction gene transcription and activated inflammation pathways, suggesting that REEP6 maintains ER and Golgi function required for expression of membrane phototransduction proteins. CRISPR/Cas9 Reep6 knockout mouse; in vitro REEP6 overexpression with ER/Golgi marker imaging; Western blot; RNA-seq; electroretinography bioRxivpreprint Medium bio_10.1101_2025.03.02.641069

Source papers

Stage 0 corpus · 47 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Identification of a functional transposon insertion in the maize domestication gene tb1. Nature genetics 555 21946354
2006 A distant upstream enhancer at the maize domestication gene tb1 has pleiotropic effects on plant and inflorescent architecture. Nature genetics 280 16642024
2003 Pattern of diversity in the genomic region near the maize domestication gene tb1. Proceedings of the National Academy of Sciences of the United States of America 187 14701910
2006 Phylogenetic analysis of the "ECE" (CYC/TB1) clade reveals duplications predating the core eudicots. Proceedings of the National Academy of Sciences of the United States of America 151 16754863
2016 Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa. American journal of human genetics 104 27889058
2011 Evolution and diversification of the CYC/TB1 gene family in Asteraceae--a comparative study in Gerbera (Mutisieae) and sunflower (Heliantheae). Molecular biology and evolution 100 22101417
2017 REEP6 deficiency leads to retinal degeneration through disruption of ER homeostasis and protein trafficking. Human molecular genetics 40 28475715
2011 Cereal domestication and evolution of branching: evidence for soft selection in the Tb1 orthologue of pearl millet (Pennisetum glaucum [L.] R. Br.). PloS one 35 21799845
2015 Analysis of the CYC/TB1 class of TCP transcription factors in basal angiosperms and magnoliids. The Plant journal : for cell and molecular biology 33 25557238
2017 Evolution and Expression Patterns of CYC/TB1 Genes in Anacyclus: Phylogenetic Insights for Floral Symmetry Genes in Asteraceae. Frontiers in plant science 30 28487706
2017 REEP6 mediates trafficking of a subset of Clathrin-coated vesicles and is critical for rod photoreceptor function and survival. Human molecular genetics 29 28369466
2016 The accessory proteins REEP5 and REEP6 refine CXCR1-mediated cellular responses and lung cancer progression. Scientific reports 27 27966653
2014 Regulation of a novel isoform of Receptor Expression Enhancing Protein REEP6 in rod photoreceptors by bZIP transcription factor NRL. Human molecular genetics 27 24691551
2018 Evolutionary diversification of CYC/TB1-like TCP homologs and their recruitment for the control of branching and floral morphology in Papaveraceae (basal eudicots). The New phytologist 24 29949661
2008 Patterns of molecular evolution associated with two selective sweeps in the Tb1-Dwarf8 region in maize. Genetics 24 18780751
2020 A CYC/TB1-type TCP transcription factor controls spikelet meristem identity in barley. Journal of experimental botany 23 32915968
2022 REEP6 knockout leads to defective β-adrenergic signaling in adipocytes and promotes obesity-related metabolic dysfunction. Metabolism: clinical and experimental 22 35150731
2014 The effect of altered dosage of a mutant allele of Teosinte branched 1 (tb1-ref) on the root system of modern maize. BMC genetics 22 24524734
1988 Specificity of Mycobacterium tuberculosis phenolic glycolipid (PGL-Tb1) antiserum. Annales de l'Institut Pasteur. Microbiology 19 2472828
2005 Deleted in polyposis 1-like 1 gene (Dp1l1): a novel gene richly expressed in retinal ganglion cells. Investigative ophthalmology & visual science 14 15728532
2021 Autosomal Recessive Retinitis Pigmentosa Associated with Three Novel REEP6 Variants in Chinese Population. Genes 13 33917198
2017 Synthesis and immunogenicity of PG-tb1 monovalent glycoconjugate. European journal of medicinal chemistry 13 28411454
2023 Comparison of interferon-gamma production between TB1 and TB2 tubes of QuantiFERON-TB Gold Plus: a meta-analysis. Clinical chemistry and laboratory medicine 11 37221870
2021 Transcript isoforms of Reep6 have distinct functions in the retina. Human molecular genetics 10 34104971
2020 TB1: from domestication gene to tool for many trades. Journal of experimental botany 10 32761247
2018 Characterization of specific CD4 and CD8 T-cell responses in QuantiFERON TB Gold-Plus TB1 and TB2 tubes. Tuberculosis (Edinburgh, Scotland) 10 30514508
2015 Natural variation in teosinte at the domestication locus teosinte branched1 (tb1). PeerJ 10 25909039
2014 A toolbox for tuberculosis (TB) diagnosis: an Indian multi-centric study (2006-2008); evaluation of serological assays based on PGL-Tb1 and ESAT-6/CFP10 antigens for TB diagnosis. PloS one 10 24797271
2022 The 'Candidatus Phytoplasma mali' effector protein SAP11CaPm interacts with MdTCP16, a class II CYC/TB1 transcription factor that is highly expressed during phytoplasma infection. PloS one 9 36520844
2019 Novel REEP6 gene mutation associated with autosomal recessive retinitis pigmentosa. Documenta ophthalmologica. Advances in ophthalmology 9 31538292
2018 Molecular cloning and sequence variance analysis of the TEOSINTE BRANCHED1 (TB1) gene in bermudagrass [Cynodon dactylon (L.) Pers]. Journal of plant physiology 9 30081253
2023 Differential chromatin binding preference is the result of the neo-functionalization of the TB1 clade of TCP transcription factors in grasses. The New phytologist 7 36484138
2018 A novel nonsense variant in REEP6 is involved in a sporadic rod-cone dystrophy case. Clinical genetics 7 29120066
2009 Polymorphisms of the apoptosis-associated gene DP1L1 (deleted in polyposis 1-like 1) in colon cancer and inflammatory bowel disease. Journal of cancer research and clinical oncology 7 19924442
2022 MiR-672-5p-Mediated Upregulation of REEP6 in Spinal Dorsal Horn Participates in Bortezomib-Induced Neuropathic Pain in Rats. Neurochemical research 5 36064821
2007 Molecular cloning, expression analyses and primary evolution studies of REV- and TB1-like genes in bamboo. Tree physiology 5 17545127
1996 Optimization study of Escherichia coli TB1 cell disruption for cytochrome b5 recovery in a small-scale bead mill. Biotechnology progress 5 8857189
2020 Expression and Function Studies of CYC/TB1-Like Genes in the Asymmetric Flower Canna (Cannaceae, Zingiberales). Frontiers in plant science 3 33343594
2019 Identification and Genomic Analysis of a Pathogenic Strain of Mycoplasma hyopneumoniae (TB1) Isolated from Tibetan Pigs. DNA and cell biology 3 31329463
2018 Generation and classification of transcriptomes in two Croomia species and molecular evolution of CYC/TB1 genes in Stemonaceae. Plant diversity 2 30740572
2015 Effect of the synthesis of rice non-symbiotic hemoglobins 1 and 2 in the recombinant Escherichia coli TB1 growth. F1000Research 2 26973784
2020 Identification and expression profiling of HvMADS57 and HvD14 in a barley tb1 mutant. Journal of genetics 1 32482923
2007 Influence of oxygen defects on the crystal structure and magnetic properties of the (Tb1-xNax)MnO3-y (0<or=x<or=0.3) system. Inorganic chemistry 1 17472373
1996 Freeze/thawing and sonication of Escherichia coli TB1 cells for cytochrome b5 recovery. Bioseparation 1 8818263
2026 Clinical and genetic characterization of REEP6-associated retinopathy in a Japanese cohort. Japanese journal of ophthalmology 0 41553438
2026 WTAP mediated m6A methylation modulates retinal photoreceptor function via facilitating of REEP6, PDE6B and RDH12 translation. Science China. Life sciences 0 41796262
2026 The expression significance and non-invasive detection of REEP6 and REEP5 in prostate cancer. BMC cancer 0 42151833

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