{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:43:05Z","timestamp":1790476985801,"version":"4.1.0"},"reference-count":80,"publisher":"American Society for Clinical Investigation","issue":"1","funder":[{"name":"U.S. Department of Defense","award":["W81XWH-17-1-0143,W81XWH-15-1-0486"],"award-info":[{"award-number":["W81XWH-17-1-0143,W81XWH-15-1-0486"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["1R01-NS111588-01A1,5R01GM118847,GM124062"],"award-info":[{"award-number":["1R01-NS111588-01A1,5R01GM118847,GM124062"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,1,16]]},"abstract":"<jats:p>\n                    Gigaxonin (also known as KLHL16) is an E3 ligase adaptor protein that promotes the ubiquitination and degradation of intermediate filament (IF) proteins. Mutations in human gigaxonin cause the fatal neurodegenerative disease giant axonal neuropathy (GAN), in which IF proteins accumulate and aggregate in axons throughout the nervous system, impairing neuronal function and viability. Despite this pathophysiological significance, the upstream regulation and downstream effects of normal and aberrant gigaxonin function remain incompletely understood. Here, we report that gigaxonin is modified by\n                    <jats:italic>O<\/jats:italic>\n                    -linked \u03b2-\n                    <jats:italic>N<\/jats:italic>\n                    -acetylglucosamine (O-GlcNAc), a prevalent form of intracellular glycosylation, in a nutrient- and growth factor\u2013dependent manner. MS analyses of human gigaxonin revealed 9 candidate sites of O-GlcNAcylation, 2 of which \u2014 serine 272 and threonine 277 \u2014 are required for its ability to mediate IF turnover in gigaxonin-deficient human cell models that we created. Taken together, the results suggest that nutrient-responsive gigaxonin O-GlcNAcylation forms a regulatory link between metabolism and IF proteostasis. Our work may have significant implications for understanding the nongenetic modifiers of GAN phenotypes and for the optimization of gene therapy for this disease.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.127751","type":"journal-article","created":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T12:23:57Z","timestamp":1574771037000},"source":"Crossref","is-referenced-by-count":20,"title":["Gigaxonin glycosylation regulates intermediate filament turnover and may impact giant axonal neuropathy etiology or treatment"],"prefix":"10.1172","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9471-4471","authenticated-orcid":true,"given":"Po-Han","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Biochemistry,"},{"name":"Department of Molecular Genetics and Microbiology, and"},{"name":"Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimin","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianli","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, and"},{"name":"Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4832-8369","authenticated-orcid":true,"given":"Duc T.","family":"Huynh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, and"},{"name":"Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany J.","family":"Bisnett","sequence":"additional","affiliation":[{"name":"Department of Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5407-0141","authenticated-orcid":true,"given":"Alexander B.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, and"},{"name":"Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, and"},{"name":"Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett M.","family":"Condon","sequence":"additional","affiliation":[{"name":"Department of Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3433-903X","authenticated-orcid":true,"given":"Jen-Tsan","family":"Chi","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, and"},{"name":"Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2729-4876","authenticated-orcid":true,"given":"Michael","family":"Boyce","sequence":"additional","affiliation":[{"name":"Department of Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2020,1,16]]},"reference":[{"issue":"10","key":"B1","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1111\/j.1469-8749.2004.tb00988.x","article-title":"Giant axonal neuropathy","volume":"46","author":"Gordon","year":"2004","journal-title":"Dev Med Child Neurol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/81701"},{"issue":"6","key":"B3","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1542\/peds.49.6.894","article-title":"Giant axonal neuropathy","volume":"49","author":"Berg","year":"1972","journal-title":"Pediatrics"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/BF00686905"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-007-6396-4"},{"key":"B6","doi-asserted-by":"crossref","DOI":"10.1186\/1479-7364-7-13","article-title":"Update on the Kelch-like (KLHL) gene family","volume":"7","author":"Dhanoa","year":"2013","journal-title":"Hum Genomics"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1056"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg092"},{"key":"B9","doi-asserted-by":"crossref","DOI":"10.1186\/2051-5960-2-47","article-title":"The instability of the BTB-KELCH protein Gigaxonin causes giant axonal neuropathy and constitutes a new penetrant and specific diagnostic test","volume":"2","author":"Boizot","year":"2014","journal-title":"Acta Neuropathol Commun"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E15-09-0627"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp044"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI66387"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw081"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201696113"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060608-102511"},{"issue":"2","key":"B16","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.bbagen.2009.07.017","article-title":"The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine","volume":"1800","author":"Hanover","year":"2010","journal-title":"Biochim Biophys Acta"},{"key":"B17","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2014.00183","article-title":"Three decades of research on O-GlcNAcylation \u2014 a major nutrient sensor that regulates signaling, transcription and cellular metabolism","volume":"5","author":"Hart","year":"2014","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201501101"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nature05815"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1126\/science.1058714"},{"issue":"312","key":"B21","doi-asserted-by":"crossref","DOI":"10.1126\/stke.3122005re13","article-title":"The hexosamine signaling pathway: deciphering the \u201cO-GlcNAc code.\u201d","volume":"2005","author":"Love","year":"2005","journal-title":"Sci STKE"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-nutr-071812-161240"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.111.126490"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.45.32015"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.07.006"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.09.010"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M803198200"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M707328200"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.6.2820"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801222200"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.100471497"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.617779"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2012.00801.x"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.4161\/auto.23459"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-010-0719-8"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2009.03.008"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.4161\/worm.27043"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14242"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.797"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3109\/10409238.2014.884535"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1039\/C4CS00038B"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R114.601351"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1080\/23723556.2017.1361501"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwy027"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1098\/rsif.2017.0123"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1055\/s-2008-1071592"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/mus.24321"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08331-w"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0140157"},{"key":"B50","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/bs.mie.2015.07.009","article-title":"Degradation of the intermediate filament family by gigaxonin","volume":"569","author":"Bomont","year":"2016","journal-title":"Meth Enzymol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2008.05601.x"},{"key":"B52","doi-asserted-by":"crossref","DOI":"10.1186\/1750-1326-6-25","article-title":"Sensory-motor deficits and neurofilament disorganization in gigaxonin-null mice","volume":"6","author":"Ganay","year":"2011","journal-title":"Mol Neurodegener"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1007\/s10286-016-0365-7"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3047"},{"key":"B55","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.31807","article-title":"Site-specific glycosylation regulates the form and function of the intermediate filament cytoskeleton","volume":"7","author":"Tarbet","year":"2018","journal-title":"Elife"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1096\/fj.01-0995fje"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/nature04256"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2005.10.052"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M503396200"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw937"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M501279200"},{"key":"B62","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/bs.mie.2015.09.036","article-title":"Methods for determining the cellular functions of vimentin intermediate filaments","volume":"568","author":"Ridge","year":"2016","journal-title":"Meth Enzymol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-nutr-071812-161240"},{"issue":"1\u20132","key":"B64","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.bbagen.2004.03.016","article-title":"O-GlcNAc a sensor of cellular state: the role of nucleocytoplasmic glycosylation in modulating cellular function in response to nutrition and stress","volume":"1673","author":"Zachara","year":"2004","journal-title":"Biochim Biophys Acta"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e07-11-1146"},{"issue":"6","key":"B66","doi-asserted-by":"crossref","first-page":"4465","DOI":"10.1016\/S0021-9258(18)53632-2","article-title":"Mitotic arrest-associated enhancement of O-linked glycosylation and phosphorylation of human keratins 8 and 18","volume":"268","author":"Chou","year":"1993","journal-title":"J Biol Chem"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.13.8752"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005158"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu556"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1172\/JCI129788"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0095"},{"issue":"269","key":"B72","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.2004088","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal","volume":"6","author":"Gao","year":"2013","journal-title":"Sci Signal"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-1776"},{"issue":"1","key":"B74","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1165\/rcmb.2013-0314TR","article-title":"The role of vimentin intermediate filaments in the progression of lung cancer","volume":"50","author":"Kidd","year":"2014","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-016-1659-5"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2018.02.005"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2012.107"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw936"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1106"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3047"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/127751\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:19:20Z","timestamp":1779193160000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/127751"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,16]]},"references-count":80,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1,16]]},"published-print":{"date-parts":[[2020,1,16]]}},"alternative-id":["10.1172\/jci.insight.127751"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.127751","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,16]]},"article-number":"e127751"}}