{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:31:06Z","timestamp":1790836266711,"version":"4.1.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T00:00:00Z","timestamp":1622764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17K08657"],"award-info":[{"award-number":["17K08657"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K06854"],"award-info":[{"award-number":["21K06854"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17F17418"],"award-info":[{"award-number":["17F17418"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17K08627"],"award-info":[{"award-number":["17K08627"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K08489"],"award-info":[{"award-number":["20K08489"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP16H06276"],"award-info":[{"award-number":["JP16H06276"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Uehara Memorial Foundation, Takeda Science Foundation, Naito Foundation and SENSHIN Medical Research Foundation to H.O"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Transmembrane protein 168 (TMEM168) was found to be localized on the nuclear membrane. A heterozygous mutation (c.1616G&amp;gt;A, p. R539Q) in TMEM168 was identified in patients with Brugada syndrome. This mutation reduced expression of cardiomyocyte sodium channel Nav1.5 via Nedd4-2 E3 ubiquitin ligase-induced ubiquitination and degradation. However, the detailed molecular mechanism provoked by the TMEM168 mutant remains unclear. Here, we demonstrated that small heat shock protein \u03b1B-crystallin, which can bind to Nav1.5 and Nedd4-2 and interfere with the association of both proteins, was strongly recruited from the cell surface to the perinuclear region because of the much higher affinity of \u03b1B-crystallin with the TMEM168 mutant than with wild-type TMEM168. Following knockdown of \u03b1B-crystallin in HL-1 cardiomyocytes, the interaction of Nav1.5 with Nedd4-2 was increased, despite the reduced expression of Nav1.5. Moreover, reduction of Nav1.5 expression by \u03b1B-crystallin knockdown was rescued in the presence of a proteasome inhibitor MG-132, suggesting the importance of the \u03b1B-crystallin-modulated ubiquitin\u2013proteasome system for the stability of Nav1.5 expression. Collectively, the balance of molecular interactions among Nav1.5, Nedd4-2 and \u03b1B-crystallin plays a role in the regulation of cardiomyocyte cell surface expression of Nav1.5, and the TMEM168 mutant disturbs this balance, resulting in a decrease in Nav1.5 expression.<\/jats:p>","DOI":"10.1093\/jb\/mvab066","type":"journal-article","created":{"date-parts":[[2021,6,3]],"date-time":"2021-06-03T19:49:02Z","timestamp":1622749742000},"page":"577-585","source":"Crossref","is-referenced-by-count":5,"title":["Transmembrane protein 168 mutation reduces cardiomyocyte cell surface expression of Nav1.5 through \u03b1B-crystallin intracellular dynamics"],"prefix":"10.1093","volume":"170","author":[{"given":"Le Kim Chi","family":"Nguyen","sequence":"first","affiliation":[{"name":"Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne Ern Chi","family":"Soh","sequence":"additional","affiliation":[{"name":"Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Komeno","sequence":"additional","affiliation":[{"name":"Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Sato","sequence":"additional","affiliation":[{"name":"Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6750-1668","authenticated-orcid":false,"given":"Hisakazu","family":"Ogita","sequence":"additional","affiliation":[{"name":"Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,4]]},"reference":[{"key":"2022021007355126600_mvab066-B1","doi-asserted-by":"crossref","first-page":"6399","DOI":"10.1096\/fj.201902991R","article-title":"Identification of transmembrane protein 168 mutation in familial Brugada syndrome","volume":"34","author":"Shimizu","year":"2020","journal-title":"FASEB J."},{"key":"2022021007355126600_mvab066-B2","doi-asserted-by":"crossref","first-page":"e0189006","DOI":"10.1371\/journal.pone.0189006","article-title":"Overexpression of transmembrane protein 168 in the mouse nucleus accumbens induces anxiety and sensorimotor gating deficit","volume":"12","author":"Fu","year":"2017","journal-title":"PLoS One"},{"key":"2022021007355126600_mvab066-B3","doi-asserted-by":"crossref","first-page":"819","DOI":"10.3727\/096504018X15478559215014","article-title":"Inhibition of proliferation by knockdown of transmembrane (TMEM) 168 in glioblastoma cells via suppression of Wnt\/\u03b2-catenin pathway","volume":"27","author":"Xu","year":"2019","journal-title":"Oncol. Res"},{"key":"2022021007355126600_mvab066-B4","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1253\/circj.CJ-12-0717","article-title":"Brugada syndrome 2012","volume":"76","author":"Berne","year":"2012","journal-title":"Circ. J"},{"key":"2022021007355126600_mvab066-B5","first-page":"100468","article-title":"Brugada syndrome: a comprehensive review of pathophysiological mechanisms and risk stratification strategies","volume":"26","author":"Li","year":"2020","journal-title":"Int. J. Cardiol. Heart Vasc"},{"key":"2022021007355126600_mvab066-B6","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1016\/0735-1097(92)90253-J","article-title":"Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report","volume":"20","author":"Brugada","year":"1992","journal-title":"J. Am. Coll. 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