{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:27:53Z","timestamp":1768512473200,"version":"3.49.0"},"posted":{"date-parts":[[2024,6,7]]},"group-title":"Cell Biology","reference-count":57,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The retromer complex mediates retrograde transport of protein cargos from endosomes to the trans-Golgi network (TGN). \u03b3-secretase is a multisubunit protease that cleaves the transmembrane domain of its target proteins. Mutations in genes encoding subunits of retromer or \u03b3-secretase can cause familial Alzheimer disease (AD) and other degenerative neurological diseases. It has been reported that retromer interacts with \u03b3-secretase, but the consequences of this interaction are not known. Here, we report that retromer-mediated retrograde protein trafficking in cultured human epithelial cells is impaired by inhibition of \u03b3-secretase activity or by genetic elimination of \u03b3-secretase. \u03b3-secretase inhibitor XXI and knockout of PS1, the catalytic subunit of \u03b3-secretase, inhibit endosome to TGN trafficking of retromer-dependent retrograde cargos, divalent metal transporter 1 isoform II (DMT1-II), cation-independent mannose-6-phosphate receptor (CIMPR), and shiga toxin. Trafficking of retromer-independent cargos, such as cholera toxin and a CIMPR mutant that does not bind to retromer was not affected by \u03b3-secretase inhibition. XXI treatment and PS1 KO inhibit interaction of \u03b3-secretase with retromer but do not inhibit the association of cargo with retromer or with \u03b3-secretase in intact cells. Similarly, these treatments do not affect the level of Rab7-GTP, which regulates retromer-cargo interaction. These results suggest that the \u03b3-secretase-retromer interaction facilitates retromer-mediated retrograde trafficking.<\/jats:p>","DOI":"10.1101\/2024.06.07.597932","type":"posted-content","created":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T19:15:11Z","timestamp":1717787711000},"source":"Crossref","is-referenced-by-count":0,"title":["\u03b3-secretase facilitates retromer-mediated retrograde transport"],"prefix":"10.64898","author":[{"given":"Yuka","family":"Takeo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mac","family":"Crite","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"DiMaio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024061104101458000_2024.06.07.597932v1.1","doi-asserted-by":"crossref","unstructured":"Burd, C. and P.J. Cullen , Retromer: a master conductor of endosome sorting. Cold Spring Harb Perspect Biol, 2014. 6(2).","DOI":"10.1101\/cshperspect.a016774"},{"key":"2024061104101458000_2024.06.07.597932v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2020.12.009"},{"key":"2024061104101458000_2024.06.07.597932v1.3","doi-asserted-by":"crossref","first-page":"897688","DOI":"10.3389\/fnagi.2022.897688","article-title":"Beware of Misdelivery: Multifaceted Role of Retromer Transport in Neurodegenerative Diseases","volume":"14","year":"2022","journal-title":"Front Aging Neurosci"},{"key":"2024061104101458000_2024.06.07.597932v1.4","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201105109"},{"key":"2024061104101458000_2024.06.07.597932v1.5","doi-asserted-by":"publisher","DOI":"10.1159\/000335910"},{"key":"2024061104101458000_2024.06.07.597932v1.6","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2018.00079"},{"issue":"3","key":"2024061104101458000_2024.06.07.597932v1.7","doi-asserted-by":"crossref","first-page":"110262","DOI":"10.1016\/j.celrep.2021.110262","article-title":"The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer\u2019s disease","volume":"38","year":"2022","journal-title":"Cell Rep"},{"key":"2024061104101458000_2024.06.07.597932v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.04.002"},{"issue":"1","key":"2024061104101458000_2024.06.07.597932v1.9","first-page":"79-92","article-title":"Endosome to Golgi retrieval of the vacuolar protein sorting receptor","volume":"137","year":"1997","journal-title":"Vps10p, requires the function of the VPS29, VPS30, and VPS35 gene products. J Cell Biol"},{"issue":"1","key":"2024061104101458000_2024.06.07.597932v1.10","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.advenzreg.2009.10.002","volume":"50","year":"2010","journal-title":"The retromer complex. Adv Enzyme Regul"},{"key":"2024061104101458000_2024.06.07.597932v1.11","doi-asserted-by":"publisher","DOI":"10.1042\/BST20140290"},{"key":"2024061104101458000_2024.06.07.597932v1.12","doi-asserted-by":"crossref","unstructured":"Guerra, F. and C. Bucci , Multiple Roles of the Small GTPase Rab7. Cells, 2016. 5(3).","DOI":"10.3390\/cells5030034"},{"key":"2024061104101458000_2024.06.07.597932v1.13","doi-asserted-by":"crossref","first-page":"129","DOI":"10.3389\/fcell.2018.00129","article-title":"This Is the End: Regulation of Rab7 Nucleotide Binding in Endolysosomal Trafficking and Autophagy","volume":"6","year":"2018","journal-title":"Front Cell Dev Biol"},{"key":"2024061104101458000_2024.06.07.597932v1.14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1316482111"},{"key":"2024061104101458000_2024.06.07.597932v1.15","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200804048"},{"key":"2024061104101458000_2024.06.07.597932v1.16","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E16-08-0582"},{"key":"2024061104101458000_2024.06.07.597932v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107750"},{"key":"2024061104101458000_2024.06.07.597932v1.18","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.103440"},{"key":"2024061104101458000_2024.06.07.597932v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.10.056"},{"key":"2024061104101458000_2024.06.07.597932v1.20","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.009654"},{"key":"2024061104101458000_2024.06.07.597932v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2022.102087"},{"key":"2024061104101458000_2024.06.07.597932v1.22","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201703015"},{"key":"2024061104101458000_2024.06.07.597932v1.23","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.003020"},{"key":"2024061104101458000_2024.06.07.597932v1.24","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.003111"},{"issue":"11","key":"2024061104101458000_2024.06.07.597932v1.25","first-page":"6382-7","article-title":"Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin","volume":"100","year":"2003","journal-title":"Aph-1, and Pen-2. Proc Natl Acad Sci U S A"},{"key":"2024061104101458000_2024.06.07.597932v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/ncb960"},{"issue":"6930","key":"2024061104101458000_2024.06.07.597932v1.27","first-page":"438-41","article-title":"The role of presenilin cofactors in the gamma-secretase complex","volume":"422","year":"2003","journal-title":"Nature"},{"issue":"7738","key":"2024061104101458000_2024.06.07.597932v1.28","first-page":"192-197","article-title":"Structural basis of Notch recognition by human gamma-secretase","volume":"565","year":"2019","journal-title":"Nature"},{"key":"2024061104101458000_2024.06.07.597932v1.29","doi-asserted-by":"crossref","unstructured":"Zhou, R. , et al., Recognition of the amyloid precursor protein by human gamma-secretase. Science, 2019. 363(6428).","DOI":"10.1126\/science.aaw0930"},{"issue":"4","key":"2024061104101458000_2024.06.07.597932v1.30","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.3233\/JAD-150940","article-title":"Non-Catalytic Roles of Presenilin Throughout Evolution","volume":"52","year":"2016","journal-title":"J Alzheimers Dis"},{"key":"2024061104101458000_2024.06.07.597932v1.31","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201804171"},{"key":"2024061104101458000_2024.06.07.597932v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/S0962-8924(98)01363-4"},{"issue":"4","key":"2024061104101458000_2024.06.07.597932v1.33","first-page":"629-631","volume":"114","year":"2017","journal-title":"Presenilin-1 mutations and Alzheimer\u2019s disease. Proc Natl Acad Sci U S A"},{"key":"2024061104101458000_2024.06.07.597932v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.06.001"},{"key":"2024061104101458000_2024.06.07.597932v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.06.008"},{"key":"2024061104101458000_2024.06.07.597932v1.36","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20667"},{"key":"2024061104101458000_2024.06.07.597932v1.37","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13586"},{"issue":"1","key":"2024061104101458000_2024.06.07.597932v1.38","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/jnc.14477","article-title":"Retrograde transport of gamma-secretase from endosomes to the trans-Golgi network regulates Abeta42 production","volume":"147","year":"2018","journal-title":"J Neurochem"},{"key":"2024061104101458000_2024.06.07.597932v1.39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1302164110"},{"key":"2024061104101458000_2024.06.07.597932v1.40","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01777-14"},{"key":"2024061104101458000_2024.06.07.597932v1.41","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004699"},{"key":"2024061104101458000_2024.06.07.597932v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.07.031"},{"key":"2024061104101458000_2024.06.07.597932v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(02)03182-4"},{"key":"2024061104101458000_2024.06.07.597932v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2012.02.012"},{"key":"2024061104101458000_2024.06.07.597932v1.45","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0954-13.2013"},{"key":"2024061104101458000_2024.06.07.597932v1.46","doi-asserted-by":"crossref","unstructured":"Seaman, M.N.J. , A.S. Mukadam , and S.Y. Breusegem , Inhibition of TBC1D5 activates Rab7a and can enhance the function of the retromer cargo-selective complex. J Cell Sci, 2018. 131(12).","DOI":"10.1242\/jcs.217398"},{"issue":"4","key":"2024061104101458000_2024.06.07.597932v1.47","first-page":"279","volume":"19","year":"2018","journal-title":"Retromer Dysfunction and Neurodegenerative Disease. Curr Genomics"},{"key":"2024061104101458000_2024.06.07.597932v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.12.009"},{"key":"2024061104101458000_2024.06.07.597932v1.49","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201797128"},{"key":"2024061104101458000_2024.06.07.597932v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(02)00076-3"},{"key":"2024061104101458000_2024.06.07.597932v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-022-00754-8"},{"issue":"11","key":"2024061104101458000_2024.06.07.597932v1.52","doi-asserted-by":"crossref","first-page":"e0166415","DOI":"10.1371\/journal.pone.0166415","article-title":"An Anti-Parkinson\u2019s Disease Drug via Targeting Adenosine A2A Receptor Enhances Amyloid-beta Generation and gamma-Secretase Activity","volume":"11","year":"2016","journal-title":"PLoS One"},{"issue":"6","key":"2024061104101458000_2024.06.07.597932v1.53","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1038\/s41380-018-0221-3","article-title":"Endosomal sorting and trafficking, the retromer complex and neurodegeneration","volume":"24","year":"2019","journal-title":"Mol Psychiatry"},{"key":"2024061104101458000_2024.06.07.597932v1.54","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0802545105"},{"key":"2024061104101458000_2024.06.07.597932v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2014.07.004"},{"key":"2024061104101458000_2024.06.07.597932v1.56","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-022-04182-9"},{"key":"2024061104101458000_2024.06.07.597932v1.57","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00757-11"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.06.07.597932","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:32:08Z","timestamp":1768458728000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.06.07.597932"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,7]]},"references-count":57,"URL":"https:\/\/doi.org\/10.1101\/2024.06.07.597932","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1242\/jcs.263538","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,6,7]]},"subtype":"preprint"}}