{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:10:17Z","timestamp":1790208617615,"version":"4.1.0"},"reference-count":73,"publisher":"SAGE Publications","issue":"7","license":[{"start":{"date-parts":[[2019,7,17]],"date-time":"2019-07-17T00:00:00Z","timestamp":1563321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,7,17]],"date-time":"2019-07-17T00:00:00Z","timestamp":1563321600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antioxidants &amp; Redox Signaling"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:sec>\n                    <jats:title>Aims:<\/jats:title>\n                    <jats:p>Histidine triad nucleotide-binding protein 1 (HINT1) exhibits proapoptotic and tumor-suppressive activity. HINT1 binds to transcription factors such as teneurin1 and to the regulator of G protein signaling 17 (RGS) (Z2) protein, which incorporates the small ubiquitin-like modifier (SUMO), and is implicated in several types of cancer. HINT1 interacts with proteins such as PKC\u03b3 and Raf-1 through zinc ions provided by the cysteine-rich domain of RGSZ2 and the coupled neural nitric oxide synthase (nNOS). Recently, a series of HINT1 mutants have been reported to cause human autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM). However, the specific alteration in the function of HINT1 induced by these mutants remains to be elucidated. Because sumoylation modifies protein association and transcriptional regulation, we investigated whether HINT1 exhibits zinc- and redox-regulated sumoylase activity, which may be altered in those mutants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>HINT1 exhibits cysteine protease activity to remove SUMO from a variety of signaling proteins. HINT1 sumoylase activity is blocked by zinc, and it is released by nitric oxide or calcium-activated calmodulin (CaM). HINT1 contains a SUMO-interacting motif (110\u2013116 HIHLHVL) and the catalytic triad Cys84-Asp87-His114 in the C-terminal region. Thus, zinc probably provided by the RGSZ2\u2013nNOS complex may bind to Cys84 to block HINT1 isopeptidase activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Innovation:<\/jats:title>\n                    <jats:p>To date, HINT1 is the only sumoylase that is regulated by two alternate pathways, redox- and calcium-activated CaM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>The 15 human HINT1 mutants reported to cause ARAN-NM exhibited altered sumoylase activity, which may contribute to the onset of this human motor disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/ars.2019.7724","type":"journal-article","created":{"date-parts":[[2019,5,15]],"date-time":"2019-05-15T07:32:20Z","timestamp":1557905540000},"page":"503-520","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":21,"title":["The Axonal Motor Neuropathy-Related HINT1 Protein Is a Zinc- and Calmodulin-Regulated Cysteine SUMO Protease"],"prefix":"10.1177","volume":"31","author":[{"given":"Elsa","family":"Cort\u00e9s-Montero","sequence":"first","affiliation":[{"name":"Neuropharmacology, Instituto Cajal, Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Rodr\u00edguez-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Neuropharmacology, Instituto Cajal, Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilar","family":"S\u00e1nchez-Bl\u00e1zquez","sequence":"additional","affiliation":[{"name":"Neuropharmacology, Instituto Cajal, Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Garz\u00f3n","sequence":"additional","affiliation":[{"name":"Neuropharmacology, Instituto Cajal, Consejo Superior de Investigaciones Cient\u00edficas (CSIC), Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,7,17]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2006.09.008"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22534"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0020897"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2011.10.082"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1515\/bchm.2001.382.5.727"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2015.01.026"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.4155\/fmc.13.91"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi025942q"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1221050110"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M804531200"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M610530200"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/iub.113"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M407005200"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2010.3767"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2011.01.017"},{"key":"e_1_3_4_17_2","first-page":"147","article-title":"The multifaceted proteins Reptin and Pontin as major players in cancer","volume":"1815","author":"Grigoletto A","year":"2011","unstructured":"Grigoletto A, , Lestienne P, , and Rosenbaum J. 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