{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:43:15Z","timestamp":1791222195422,"version":"4.1.0"},"reference-count":47,"publisher":"American Diabetes Association","issue":"12","license":[{"start":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T00:00:00Z","timestamp":1727308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/100000062","name":"NIDDK","doi-asserted-by":"crossref","award":["R01 DK12044"],"award-info":[{"award-number":["R01 DK12044"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"NIDDK","doi-asserted-by":"crossref","award":["R01 DK132387"],"award-info":[{"award-number":["R01 DK132387"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"NIDDK","doi-asserted-by":"crossref","award":["SCR014393"],"award-info":[{"award-number":["SCR014393"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"NIDDK","doi-asserted-by":"crossref","award":["UC24 DK104162"],"award-info":[{"award-number":["UC24 DK104162"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Key R&D Program","award":["2019YFA0802502"],"award-info":[{"award-number":["2019YFA0802502"]}]},{"name":"National Key R&D Program","award":["2022YFE0131400"],"award-info":[{"award-number":["2022YFE0131400"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82000796"],"award-info":[{"award-number":["82000796"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82370821"],"award-info":[{"award-number":["82370821"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH","award":["K01 DK133533"],"award-info":[{"award-number":["K01 DK133533"]}]},{"name":"NIH","award":["R01 DK111174"],"award-info":[{"award-number":["R01 DK111174"]}]},{"name":"NIH","award":["R01 DK48280"],"award-info":[{"award-number":["R01 DK48280"]}]},{"name":"NIH","award":["R15 GM120659"],"award-info":[{"award-number":["R15 GM120659"]}]},{"name":"NIH","award":["R21 AI154254"],"award-info":[{"award-number":["R21 AI154254"]}]},{"name":"NIH","award":["U01 DK127747"],"award-info":[{"award-number":["U01 DK127747"]}]},{"DOI":"10.13039\/100022690","name":"JDRF","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100022690","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,12,1]]},"abstract":"<jats:sec>\n                  <jats:title\/>\n                  <jats:p>Translocational regulation of proinsulin biosynthesis in pancreatic \u03b2-cells is unknown, although several studies have reported an important accessory role for the Translocon-Associated Protein complex to assist preproinsulin delivery into the endoplasmic reticulum via the heterotrimeric Sec61 translocon (comprising \u03b1, \u03b2, and \u03b3 subunits). The actual protein-conducting channel is the \u03b1-subunit encoded either by Sec61A1 or its paralog Sec61A2. Although the underlying channel selectivity for preproinsulin translocation is unknown, almost all studies of Sec61\u03b1 to date have focused on Sec61\u03b11. There is currently no evidence to suggest that this gene product plays a major role in proinsulin production, whereas genome-wide association studies indicate linkage of Sec61A2 with diabetes. Here, we report that evolutionary differences in mouse preproinsulin signal peptides affect proinsulin biosynthesis. Moreover, we find that, although some preproinsulin translocation can proceed through Sec61\u03b11, Sec61\u03b12 has a greater impact on proinsulin biosynthesis in pancreatic \u03b2-cells. Remarkably, Sec61\u03b12 translocon deficiency exerts a significant inhibitory effect on the biosynthesis of preproinsulin itself, including a disproportionate increase of full-length nascent chain unreleased from ribosomes. This study not only reveals novel translocational regulation of proinsulin biosynthesis but also provides a rationale for genetic evidence suggesting an important role of Sec61\u03b12 in maintaining blood glucose homeostasis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Article Highlights<\/jats:title>\n               <\/jats:sec>","DOI":"10.2337\/db24-0115","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T16:27:22Z","timestamp":1727368042000},"page":"2034-2044","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":9,"title":["Role of Sec61\u03b12 Translocon in Insulin Biosynthesis"],"prefix":"10.2337","volume":"73","author":[{"given":"Xiaoxi","family":"Xu","sequence":"first","affiliation":[{"name":"1Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI"},{"name":"2Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas W.","family":"Bell","sequence":"additional","affiliation":[{"name":"3Department of Chemistry, University of Nevada, Reno, NV"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Truc","family":"Le","sequence":"additional","affiliation":[{"name":"3Department of Chemistry, University of Nevada, Reno, NV"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivy","family":"Zhao","sequence":"additional","affiliation":[{"name":"1Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Walker","sequence":"additional","affiliation":[{"name":"1Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqing","family":"Wang","sequence":"additional","affiliation":[{"name":"2Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Xu","sequence":"additional","affiliation":[{"name":"2Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"Soleimanpour","sequence":"additional","affiliation":[{"name":"1Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger A.","family":"Russ","sequence":"additional","affiliation":[{"name":"4Diabetes Institute, University of Florida College of Medicine, Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Qi","sequence":"additional","affiliation":[{"name":"5Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Billy","family":"Tsai","sequence":"additional","affiliation":[{"name":"6Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Liu","sequence":"additional","affiliation":[{"name":"2Department 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":"1Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2024,9,26]]},"reference":[{"key":"2024112019512508900_B1","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1126\/science.aad4992","article-title":"Structure of the Sec61 channel opened by a signal sequence","volume":"351","author":"Voorhees","year":"2016","journal-title":"Science"},{"key":"2024112019512508900_B2","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(Suppl 2)","author":"Liu","year":"2018","journal-title":"Diabetes Obes Metab"},{"key":"2024112019512508900_B3","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 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reticulum","volume":"71","author":"Xu","year":"2021","journal-title":"Diabetes"},{"key":"2024112019512508900_B7","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":"2024112019512508900_B8","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":"2024112019512508900_B9","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/nature12950","article-title":"Structures of the Sec61 complex engaged in nascent peptide translocation or membrane 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Evidence for regulation of elongation, initiation and signal-recognition-particle-mediated translational arrest by glucose","volume":"235","author":"Welsh","year":"1986","journal-title":"Biochem J"},{"key":"2024112019512508900_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"},{"key":"2024112019512508900_B32","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/B978-0-12-800174-5.00002-8","article-title":"Proinsulin entry and transit through the endoplasmic reticulum in pancreatic beta cells","volume":"95","author":"Liu","year":"2014","journal-title":"Vitam Horm"},{"key":"2024112019512508900_B33","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":"2024112019512508900_B34","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/s41574-021-00510-4","article-title":"Therapeutic opportunities for pancreatic \u03b2-cell ER stress in diabetes mellitus","volume":"17","author":"Yong","year":"2021","journal-title":"Nat Rev Endocrinol"},{"key":"2024112019512508900_B35","doi-asserted-by":"crossref","first-page":"650158","DOI":"10.3389\/fendo.2021.650158","article-title":"Pathological \u03b2-cell endoplasmic reticulum stress in type 2 diabetes: current evidence","volume":"12","author":"Shrestha","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2024112019512508900_B36","doi-asserted-by":"crossref","first-page":"7823","DOI":"10.1073\/pnas.141125098","article-title":"Substrate-specific regulation of the ribosome- translocon junction by N-terminal signal sequences","volume":"98","author":"Rutkowski","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2024112019512508900_B37","doi-asserted-by":"crossref","first-page":"30365","DOI":"10.1074\/jbc.M302117200","article-title":"Signal sequences initiate the pathway of maturation in the endoplasmic reticulum lumen","volume":"278","author":"Rutkowski","year":"2003","journal-title":"J Biol Chem"},{"key":"2024112019512508900_B38","doi-asserted-by":"crossref","first-page":"e75394","DOI":"10.1371\/journal.pone.0075394","article-title":"The signal sequence influences post-translational ER translocation at distinct stages","volume":"8","author":"Johnson","year":"2013","journal-title":"PLoS One"},{"key":"2024112019512508900_B39","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/j.celrep.2018.03.122","article-title":"Chaperone-mediated Sec61 channel gating during ER import of small precursor proteins overcomes Sec61 inhibitor-reinforced energy barrier","volume":"23","author":"Ha\u00dfdenteufel","year":"2018","journal-title":"Cell Rep"},{"key":"2024112019512508900_B40","doi-asserted-by":"crossref","first-page":"bio040691","DOI":"10.1242\/bio.040691","article-title":"The signal peptide plus a cluster of positive charges in prion protein dictate chaperone-mediated Sec61 channel gating","volume":"8","author":"Ziska","year":"2019","journal-title":"Biol Open"},{"key":"2024112019512508900_B41","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":"2024112019512508900_B42","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.jmb.2006.05.023","article-title":"The geometry of the ribosomal polypeptide exit tunnel","volume":"360","author":"Voss","year":"2006","journal-title":"J Mol Biol"},{"key":"2024112019512508900_B43","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/s42003-021-02055-8","article-title":"The ribosome modulates folding inside the ribosomal exit tunnel","volume":"4","author":"Wruck","year":"2021","journal-title":"Commun Biol"},{"key":"2024112019512508900_B44","doi-asserted-by":"crossref","first-page":"014409","DOI":"10.1103\/PhysRevE.105.014409","article-title":"Ribosome exit tunnel electrostatics","volume":"105","author":"Joiret","year":"2022","journal-title":"Phys Rev E"},{"key":"2024112019512508900_B45","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1126\/science.1261909","article-title":"Ribosome. Mechanical force releases nascent chain-mediated ribosome arrest in\u00a0vitro and in\u00a0vivo","volume":"348","author":"Goldman","year":"2015","journal-title":"Science"},{"key":"2024112019512508900_B46","doi-asserted-by":"crossref","first-page":"7478","DOI":"10.1016\/S0021-9258(19)39138-0","article-title":"Truncations of a secretory protein define minimum lengths required for binding to signal recognition particle and translocation across the endoplasmic reticulum membrane","volume":"265","author":"Okun","year":"1990","journal-title":"J Biol Chem"},{"key":"2024112019512508900_B47","doi-asserted-by":"crossref","first-page":"e108299","DOI":"10.15252\/embj.2021108299","article-title":"Nascent polypeptide within the exit tunnel stabilizes the ribosome to counteract risky translation","volume":"40","author":"Chadani","year":"2021","journal-title":"Embo J"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/73\/12\/2034\/789545\/db240115.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/73\/12\/2034\/789545\/db240115.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T19:52:10Z","timestamp":1732132330000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/73\/12\/2034\/157297\/Role-of-Sec61-2-Translocon-in-Insulin-Biosynthesis"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,26]]},"references-count":47,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,9,26]]},"published-print":{"date-parts":[[2024,12,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db24-0115","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,26]]}}}