{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T16:34:20Z","timestamp":1786466060117,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,10]]},"group-title":"Cell Biology","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["219531\/Z\/19Z"],"award-info":[{"award-number":["219531\/Z\/19Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["320911\/Z\/24\/Z"],"award-info":[{"award-number":["320911\/Z\/24\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"crossref","award":["BB\/Z517215\/1"],"award-info":[{"award-number":["BB\/Z517215\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["ZIA NS003139"],"award-info":[{"award-number":["ZIA NS003139"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Selective export of membrane proteins from the endoplasmic reticulum (ER) is fundamental for eukaryotic cell biology, yet how trafficking receptors coordinate cargo recognition with membrane adaptation and COPII recruitment remains unknown. Cornichon homolog (CNIH) proteins comprise a conserved family of trafficking receptors that mediate ER export of ion channels, G protein-coupled receptors (GPCRs), ATP-binding cassette (ABC) and solute carrier (SLC) transporters. Here, we determine cryo-electron microscopy structures of the prototypical cornichon receptor Erv14 bound to an SLC transporter in detergent and lipid nanodiscs. We show that cargo recognition is mediated by a dynamic network of interactions, in which structural lipids stabilize the receptor-cargo interface. Nanodisc structures reveal the assembly of a second Erv14 receptor that remodels the receptor-cargo interface in response to membrane architecture, thereby reducing local membrane thickness and providing direct structural evidence that cornichon receptors buffer hydrophobic mismatch during membrane protein biogenesis. Structural and trafficking analyses further show that the second receptor recruits the COPII adaptor Sec24, coupling membrane remodelling to cargo export. Together, our findings establish that cornichon receptors couple lipid-mediated membrane adaptation with cargo selection through sequential receptor assembly, linking membrane protein folding to selective COPII-mediated ER export.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One sentence summary<\/jats:title>\n                  <jats:p>Cornichon receptors integrate membrane adaptation with cargo recognition to coordinate membrane protein quality control and selective ER export.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.08.07.743479","type":"posted-content","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T12:55:16Z","timestamp":1786366516000},"source":"Crossref","is-referenced-by-count":0,"title":["Cornichon receptors couple membrane adaptation to cargo selection during ER export"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0921-9696","authenticated-orcid":false,"given":"Jude","family":"Tunyi","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Oxford, Oxford, UK"},{"name":"Kavli Institute of Nanoscience Discovery, University of Oxford, Oxford, UK"},{"name":"Computational Structural Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5145-9589","authenticated-orcid":false,"given":"Oliver","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Oxford, Oxford, UK"},{"name":"Kavli Institute of Nanoscience Discovery, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si\u00e2n","family":"Holton","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Oxford, Oxford, UK"},{"name":"Kavli Institute of Nanoscience Discovery, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2648-6593","authenticated-orcid":false,"given":"Martyna","family":"Biadu\u0144","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Oxford, Oxford, UK"},{"name":"Kavli Institute of Nanoscience Discovery, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4309-4644","authenticated-orcid":false,"given":"Nathan","family":"Bernhardt","sequence":"additional","affiliation":[{"name":"Computational Structural Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Kuteyi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Oxford, Oxford, UK"},{"name":"Kavli Institute of Nanoscience Discovery, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6538-9059","authenticated-orcid":false,"given":"Omar","family":"Pantoja","sequence":"additional","affiliation":[{"name":"Instituto de Biotecnolog\u00eda, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Av. Universidad 2001, Cuernavaca, Morelos, 62210, M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1855-7985","authenticated-orcid":false,"given":"Lucy R.","family":"Forrest","sequence":"additional","affiliation":[{"name":"Computational Structural Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2964-2720","authenticated-orcid":false,"given":"Joanne L.","family":"Parker","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Oxford, Oxford, UK"},{"name":"Kavli Institute of Nanoscience Discovery, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7432-2270","authenticated-orcid":false,"given":"Simon","family":"Newstead","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Oxford, Oxford, UK"},{"name":"Kavli Institute of Nanoscience Discovery, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026081108301119000_2026.08.07.743479v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-111315-125016"},{"key":"2026081108301119000_2026.08.07.743479v1.2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.8b00532"},{"key":"2026081108301119000_2026.08.07.743479v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2011.05.006"},{"key":"2026081108301119000_2026.08.07.743479v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2022.02.012"},{"key":"2026081108301119000_2026.08.07.743479v1.5","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021014-071838"},{"key":"2026081108301119000_2026.08.07.743479v1.6","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.570200"},{"key":"2026081108301119000_2026.08.07.743479v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90148-8"},{"key":"2026081108301119000_2026.08.07.743479v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90138-4"},{"key":"2026081108301119000_2026.08.07.743479v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00609-3"},{"key":"2026081108301119000_2026.08.07.743479v1.10","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1038\/s41580-025-00839-y","article-title":"Mechanisms of COPII coat assembly and cargo recognition in the secretory pathway","volume":"26","year":"2025","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026081108301119000_2026.08.07.743479v1.11","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12817"},{"key":"2026081108301119000_2026.08.07.743479v1.12","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.112.142810"},{"key":"2026081108301119000_2026.08.07.743479v1.13","doi-asserted-by":"crossref","unstructured":"L. Smalinskaite , R. S. Hegde , The Biogenesis of Multipass Membrane Proteins. Cold Spring Harb Perspect Biol 15, (2023).","DOI":"10.1101\/cshperspect.a041251"},{"key":"2026081108301119000_2026.08.07.743479v1.14","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.76.061705.130002"},{"key":"2026081108301119000_2026.08.07.743479v1.15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001329"},{"key":"2026081108301119000_2026.08.07.743479v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-4157(98)00017-3"},{"key":"2026081108301119000_2026.08.07.743479v1.17","doi-asserted-by":"crossref","unstructured":"S. Rodriguez-Gallardo et al., Ceramide chain length-dependent protein sorting into selective endoplasmic reticulum exit sites. Sci Adv 6, (2020).","DOI":"10.1126\/sciadv.aba8237"},{"key":"2026081108301119000_2026.08.07.743479v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2020.07.059"},{"key":"2026081108301119000_2026.08.07.743479v1.19","doi-asserted-by":"crossref","unstructured":"I. Castello-Serrano , S. Dagar , R. Ippolito , K. R. Levental , I. Levental , ER exit sites mediated by the COPII adaptor sec24D selectively recruit lipid raft-preferring proteins for rapid ER export. Nat Commun 16, 10694 (2025).","DOI":"10.1038\/s41467-025-65726-8"},{"key":"2026081108301119000_2026.08.07.743479v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90016-0"},{"key":"2026081108301119000_2026.08.07.743479v1.21","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02219"},{"key":"2026081108301119000_2026.08.07.743479v1.22","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.004200"},{"key":"2026081108301119000_2026.08.07.743479v1.23","doi-asserted-by":"publisher","DOI":"10.1126\/science.1167852"},{"key":"2026081108301119000_2026.08.07.743479v1.24","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12148"},{"key":"2026081108301119000_2026.08.07.743479v1.25","doi-asserted-by":"crossref","unstructured":"J. Zheng , L. Yao , X. Zeng , B. Wang , L. Pan , ERV14 receptor impacts mycelial growth via its interactions with cell wall synthase and transporters in Aspergillus niger. Front Microbiol 14, 1128462 (2023).","DOI":"10.3389\/fmicb.2023.1128462"},{"key":"2026081108301119000_2026.08.07.743479v1.26","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1016\/j.bbamcr.2019.05.005","article-title":"Erv14 cargo receptor participates in regulation of plasma-membrane potential, intracellular pH and potassium homeostasis via its interaction with K(+)-specific transporters Trk1 and Tok1","volume":"1866","year":"2019","journal-title":"Biochim Biophys Acta Mol Cell Res"},{"key":"2026081108301119000_2026.08.07.743479v1.27","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.bbamem.2015.09.024","article-title":"Erv14 cargo receptor participates in yeast salt tolerance via its interaction with the plasma-membrane Nha1 cation\/proton antiporter","volume":"1858","year":"2016","journal-title":"Biochim Biophys Acta"},{"key":"2026081108301119000_2026.08.07.743479v1.28","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.03405"},{"key":"2026081108301119000_2026.08.07.743479v1.29","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.01-10-0499"},{"key":"2026081108301119000_2026.08.07.743479v1.30","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1016\/j.bbamcr.2017.07.004","article-title":"Plant and yeast cornichon possess a conserved acidic motif required for correct targeting of plasma membrane cargos","volume":"1864","year":"2017","journal-title":"Biochim Biophys Acta Mol Cell Res"},{"key":"2026081108301119000_2026.08.07.743479v1.31","doi-asserted-by":"publisher","DOI":"10.1002\/pro.70483"},{"key":"2026081108301119000_2026.08.07.743479v1.32","doi-asserted-by":"crossref","unstructured":"L. Y. Yen et al., Auxiliary subunits reshape structural asymmetry and functional plasticity in heterotetrameric GluA1\/A2 AMPA receptor core. Nat Commun 17, (2026).","DOI":"10.1038\/s41467-026-71063-1"},{"key":"2026081108301119000_2026.08.07.743479v1.33","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1038\/s41594-023-01080-x","article-title":"Modulation of GluA2-gamma5 synaptic complex desensitization, polyamine block and antiepileptic perampanel inhibition by auxiliary subunit cornichon-2","volume":"30","year":"2023","journal-title":"Nat Struct Mol Biol"},{"key":"2026081108301119000_2026.08.07.743479v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03613-0"},{"key":"2026081108301119000_2026.08.07.743479v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03540-0"},{"key":"2026081108301119000_2026.08.07.743479v1.36","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41422-026-01234-8","article-title":"Assembly and gating mechanism of native AMPA receptors from the cerebellum","volume":"36","year":"2026","journal-title":"Cell Res"},{"key":"2026081108301119000_2026.08.07.743479v1.37","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay2783"},{"key":"2026081108301119000_2026.08.07.743479v1.38","doi-asserted-by":"crossref","unstructured":"D. Lagunas-G\u00f3mez , C. Y\u00e1\u00f1ez-Dom\u00ednguez , G. Zavala-Padilla , C. Barlowe , O. Pantoja , The C-terminus of the cargo receptor Erv14p affects COPII vesicle formation and cargo delivery. Journal of Cell Science 136, (2023).","DOI":"10.1242\/jcs.260527"},{"key":"2026081108301119000_2026.08.07.743479v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/S0962-8924(03)00082-5"},{"key":"2026081108301119000_2026.08.07.743479v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2024.04.024"},{"key":"2026081108301119000_2026.08.07.743479v1.41","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.61.080706.093329"},{"key":"2026081108301119000_2026.08.07.743479v1.42","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biophys-060414-033901"},{"key":"2026081108301119000_2026.08.07.743479v1.43","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/s44320-025-00108-2","article-title":"Data- and knowledge-derived functional landscape of human solute carriers","volume":"21","year":"2025","journal-title":"Mol Syst Biol"},{"key":"2026081108301119000_2026.08.07.743479v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/nature13116"},{"key":"2026081108301119000_2026.08.07.743479v1.45","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.0c00983"},{"key":"2026081108301119000_2026.08.07.743479v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2003.10.014"},{"key":"2026081108301119000_2026.08.07.743479v1.47","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/j.cub.2018.02.020","article-title":"Architecture of Lipid Droplets in Endoplasmic Reticulum Is Determined by Phospholipid Intrinsic Curvature","volume":"28","year":"2018","journal-title":"Curr Biol"},{"key":"2026081108301119000_2026.08.07.743479v1.48","doi-asserted-by":"crossref","unstructured":"X. Li et al., Bilayer thickness and transmembrane domain dynamics drive directional ER-Golgi traffic via Erv14\/cornichon. bioRxiv, (2026).","DOI":"10.64898\/2026.08.05.742935"},{"key":"2026081108301119000_2026.08.07.743479v1.49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0704546104"},{"key":"2026081108301119000_2026.08.07.743479v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(01)02980-5"},{"key":"2026081108301119000_2026.08.07.743479v1.51","doi-asserted-by":"publisher","DOI":"10.1126\/science.1167983"},{"key":"2026081108301119000_2026.08.07.743479v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00608-1"},{"key":"2026081108301119000_2026.08.07.743479v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2014.11.070"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.08.07.743479","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T15:30:20Z","timestamp":1786462220000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.08.07.743479"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":53,"URL":"https:\/\/doi.org\/10.64898\/2026.08.07.743479","relation":{},"subject":[],"published":{"date-parts":[[2026,8,10]]},"subtype":"preprint"}}