{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T04:00:21Z","timestamp":1788580821732,"version":"build-2803163510"},"reference-count":31,"publisher":"American Diabetes Association","issue":"3","license":[{"start":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T00:00:00Z","timestamp":1638403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/content\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,3,1]]},"abstract":"<jats:p>In the endoplasmic reticulum (ER), the translocation-associated protein complex (TRAP), also called signal sequence receptor (SSR), includes four integral membrane proteins TRAP\u03b1\/SSR1, TRAP\u03b2\/SSR2, and TRAP\u03b4\/SSR4 with the bulk of their extramembranous portions primarily in the ER lumen, whereas the extramembranous portion of TRAP\u03b3\/SSR3 is primarily cytosolic. Individually diminished expression of either TRAP\u03b1\/SSR1, TRAP\u03b2\/SSR2, or TRAP\u03b4\/SSR4 mRNA is known in each case to lower TRAP\u03b1\/SSR1 protein levels, leading to impaired proinsulin biosynthesis, whereas forced expression of TRAP\u03b1\/SSR1 at least partially suppresses the proinsulin biosynthetic defect. Here, we report that diminished TRAP\u03b3\/SSR3 expression in pancreatic \u03b2-cells leaves TRAP\u03b1\/SSR1 levels unaffected while nevertheless inhibiting cotranslational and posttranslational translocation of preproinsulin into the ER. Crucially, acute exposure to high glucose leads to a rapid upregulation of both TRAP\u03b3\/SSR3 and proinsulin protein without change in the respective mRNA levels, as observed in cultured rodent \u03b2-cell lines and confirmed in human islets. Strikingly, pancreatic \u03b2-cells with suppressed TRAP\u03b3\/SSR3 expression are blocked in glucose-dependent upregulation of proinsulin (or insulin) biosynthesis. Most remarkably, overexpression of TRAP\u03b3\/SSR3 in control \u03b2-cells raises proinsulin levels, even without boosting extracellular glucose. The data suggest the possibility that TRAP\u03b3\/SSR3 may fulfill a rate-limiting function in preproinsulin translocation across the ER membrane for proinsulin biosynthesis.<\/jats:p>","DOI":"10.2337\/db21-0638","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T12:07:12Z","timestamp":1638446832000},"page":"440-452","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":15,"title":["The Role of TRAP\u03b3\/SSR3 in Preproinsulin Translocation Into the Endoplasmic Reticulum"],"prefix":"10.2337","volume":"71","author":[{"given":"Xiaoxi","family":"Xu","sequence":"first","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, MI"},{"name":"Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumeng","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, MI"},{"name":"Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, MI"},{"name":"Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4007-8799","authenticated-orcid":false,"given":"Peter","family":"Arvan","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2665-4072","authenticated-orcid":false,"given":"Ming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"key":"2022031309594055300_B1","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1038\/s41588-018-0241-6","article-title":"Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps","volume":"50","author":"Mahajan","year":"2018","journal-title":"Nat Genet"},{"key":"2022031309594055300_B2","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/ng.2897","article-title":"Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility","volume":"46","author":"Mahajan","year":"2014","journal-title":"Nat Genet"},{"key":"2022031309594055300_B3","doi-asserted-by":"crossref","first-page":"eaax0292","DOI":"10.1126\/sciadv.aax0292","article-title":"Requirement for translocon-associated protein (TRAP) \u03b1 in insulin biogenesis","volume":"5","author":"Li","year":"2019","journal-title":"Sci Adv"},{"key":"2022031309594055300_B4","doi-asserted-by":"crossref","first-page":"166694","DOI":"10.1016\/j.jmb.2020.10.028","article-title":"Translocon-associated protein complex (TRAP) is crucial for co-translational translocation of pre-proinsulin","volume":"432","author":"Kriegler","year":"2020","journal-title":"J Mol Biol"},{"key":"2022031309594055300_B5","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.1073\/pnas.85.11.3865","article-title":"Glucose stimulates proinsulin biosynthesis by a dose-dependent recruitment of pancreatic beta cells","volume":"85","author":"Schuit","year":"1988","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031309594055300_B6","doi-asserted-by":"crossref","first-page":"5773","DOI":"10.1073\/pnas.100126597","article-title":"Expression profiling of pancreatic beta cells: glucose regulation of secretory and metabolic pathway genes","volume":"97","author":"Webb","year":"2000","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031309594055300_B7","doi-asserted-by":"crossref","first-page":"e142240","DOI":"10.1172\/JCI142240","article-title":"Normal and defective pathways in biogenesis and maintenance of the insulin storage pool","volume":"131","author":"Liu","year":"2021","journal-title":"J Clin Invest"},{"key":"2022031309594055300_B8","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/dom.13378","article-title":"Biosynthesis, structure, and folding of the insulin precursor protein","volume":"20","author":"Liu","year":"2018","journal-title":"Diabetes Obes Metab"},{"key":"2022031309594055300_B9","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1083\/jcb.200210095","article-title":"Substrate-specific function of the translocon-associated protein complex during translocation across the ER membrane","volume":"160","author":"Fons","year":"2003","journal-title":"J Cell Biol"},{"key":"2022031309594055300_B10","doi-asserted-by":"crossref","first-page":"2792","DOI":"10.1096\/fasebj.5.13.1916103","article-title":"Protein transport across the endoplasmic reticulum membrane: facts, models, mysteries","volume":"5","author":"Rapoport","year":"1991","journal-title":"FASEB J"},{"key":"2022031309594055300_B11","doi-asserted-by":"crossref","first-page":"14516","DOI":"10.1038\/ncomms14516","article-title":"Dissecting the molecular organization of the translocon-associated protein complex","volume":"8","author":"Pfeffer","year":"2017","journal-title":"Nat Commun"},{"key":"2022031309594055300_B12","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/978-3-030-28151-9_4","article-title":"Functions and mechanisms of the human ribosome-translocon complex","volume":"93","author":"Lang","year":"2019","journal-title":"Subcell Biochem"},{"key":"2022031309594055300_B13","doi-asserted-by":"crossref","first-page":"jcs231340","DOI":"10.1242\/jcs.231340","article-title":"A clearer picture of the ER translocon complex","volume":"133","author":"Gemmer","year":"2020","journal-title":"J Cell Sci"},{"key":"2022031309594055300_B14","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/j.bbamem.2017.01.027","article-title":"Membrane insertion and topology of the translocon-associated protein (TRAP) gamma subunit","volume":"1859","author":"Ba\u00f1\u00f3-Polo","year":"2017","journal-title":"Biochim Biophys Acta Biomembr"},{"key":"2022031309594055300_B15","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1002\/jimd.12091","article-title":"Mutations in the translocon-associated protein complex subunit SSR3 cause a novel congenital disorder of glycosylation","volume":"42","author":"Ng","year":"2019","journal-title":"J Inherit Metab Dis"},{"key":"2022031309594055300_B16","doi-asserted-by":"crossref","first-page":"eabc6364","DOI":"10.1126\/sciadv.abc6364","article-title":"The translocon-associated protein (TRAP) complex regulates quality control of N-linked glycosylation during ER stress","volume":"7","author":"Phoomak","year":"2021","journal-title":"Sci Adv"},{"key":"2022031309594055300_B17","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1136\/jmedgenet-2019-106279","article-title":"TRAP\u03b3-CDG shows asymmetric glycosylation and an effect on processing of proteins required in higher organisms","volume":"58","author":"Dittner-Moormann","year":"2021","journal-title":"J Med Genet"},{"key":"2022031309594055300_B18","doi-asserted-by":"crossref","first-page":"3765","DOI":"10.1038\/s41467-018-06188-z","article-title":"Proteomics reveals signal peptide features determining the client specificity in human TRAP-dependent ER protein import","volume":"9","author":"Nguyen","year":"2018","journal-title":"Nat Commun"},{"key":"2022031309594055300_B19","doi-asserted-by":"crossref","first-page":"e21515","DOI":"10.1096\/fj.202002774R","article-title":"Deficient endoplasmic reticulum translocon-associated protein complex limits the biosynthesis of proinsulin and insulin","volume":"35","author":"Huang","year":"2021","journal-title":"FASEB J"},{"key":"2022031309594055300_B20","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1083\/jcb.111.6.2283","article-title":"The signal sequence receptor has a second subunit and is part of a translocation complex in the endoplasmic reticulum as probed by bifunctional reagents","volume":"111","author":"G\u00f6rlich","year":"1990","journal-title":"J Cell Biol"},{"key":"2022031309594055300_B21","doi-asserted-by":"crossref","first-page":"828","DOI":"10.2337\/db11-0878","article-title":"Impaired cleavage of preproinsulin signal peptide linked to autosomal-dominant diabetes","volume":"61","author":"Liu","year":"2012","journal-title":"Diabetes"},{"key":"2022031309594055300_B22","doi-asserted-by":"crossref","first-page":"424","DOI":"10.2337\/diabetes.49.3.424","article-title":"Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion","volume":"49","author":"Hohmeier","year":"2000","journal-title":"Diabetes"},{"key":"2022031309594055300_B23","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1007\/s00125-020-05192-7","article-title":"The making of insulin in health and disease","volume":"63","author":"Vasiljevi\u0107","year":"2020","journal-title":"Diabetologia"},{"key":"2022031309594055300_B24","doi-asserted-by":"crossref","first-page":"e44532","DOI":"10.7554\/eLife.44532","article-title":"Proinsulin misfolding is an early event in the progression to type 2 diabetes","volume":"8","author":"Arunagiri","year":"2019","journal-title":"eLife"},{"key":"2022031309594055300_B25","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1126\/science.aaa2628","article-title":"Insulin granules. Insulin secretory granules control autophagy in pancreatic \u03b2 cells","volume":"347","author":"Goginashvili","year":"2015","journal-title":"Science"},{"key":"2022031309594055300_B26","doi-asserted-by":"crossref","first-page":"16290","DOI":"10.1074\/jbc.M114.562355","article-title":"Inefficient translocation of preproinsulin contributes to pancreatic \u03b2 cell failure and late-onset diabetes","volume":"289","author":"Guo","year":"2014","journal-title":"J Biol Chem"},{"key":"2022031309594055300_B27","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1074\/jbc.RA117.000922","article-title":"Positive charge in the n-region of the signal peptide contributes to efficient post-translational translocation of small secretory preproteins","volume":"293","author":"Guo","year":"2018","journal-title":"J Biol Chem"},{"key":"2022031309594055300_B28","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/j.chembiol.2018.04.006","article-title":"Measuring endoplasmic reticulum signal sequences translocation efficiency using the Xbp1 arrest peptide","volume":"25","author":"Kriegler","year":"2018","journal-title":"Cell Chem Biol"},{"key":"2022031309594055300_B29","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.molcel.2012.01.016","article-title":"RNA-binding protein HuD controls insulin translation","volume":"45","author":"Lee","year":"2012","journal-title":"Mol Cell"},{"key":"2022031309594055300_B30","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/283100a0","article-title":"Translational control of proinsulin synthesis by glucose","volume":"283","author":"Itoh","year":"1980","journal-title":"Nature"},{"key":"2022031309594055300_B31","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1083\/jcb.121.6.1211","article-title":"Discrete nascent chain lengths are required for the insertion of presecretory proteins into microsomal membranes","volume":"121","author":"Wolin","year":"1993","journal-title":"J Cell Biol"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/71\/3\/440\/670148\/db210638.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/71\/3\/440\/670148\/db210638.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T12:43:26Z","timestamp":1667393006000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/71\/3\/440\/138945\/The-Role-of-TRAP-SSR3-in-Preproinsulin"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,2]]},"references-count":31,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,12,2]]},"published-print":{"date-parts":[[2022,3,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db21-0638","relation":{"has-preprint":[{"id-type":"doi","id":"10.2337\/figshare.17064434","asserted-by":"object"},{"id-type":"doi","id":"10.2337\/figshare.17064434.v1","asserted-by":"object"}]},"ISSN":["0012-1797"],"issn-type":[{"value":"0012-1797","type":"print"}],"subject":[],"published":{"date-parts":[[2021,12,2]]}}}