title: RING finger protein 121 facilitates the degradation and membrane localization of voltage-gated sodium channels.
abstract: Following their synthesis in the endoplasmic reticulum (ER), voltage-gated sodium channels (NaV) are transported to the membranes of excitable cells, where they often cluster, such as at the axon initial segment of neurons. Although the mechanisms by which NaV channels form and maintain clusters have been extensively examined, the processes that govern their transport and degradation have received less attention. Our entry into the study of these processes began with the isolation of a new allele of the zebrafish mutant alligator, which we found to be caused by mutations in the gene encoding really interesting new gene (RING) finger protein 121 (RNF121), an E3-ubiquitin ligase present in the ER and cis-Golgi compartments. Here we demonstrate that RNF121 facilitates two opposing fates of NaV channels: (i) ubiquitin-mediated proteasome degradation and (ii) membrane localization when coexpressed with auxiliary NaVβ subunits. Collectively, these results indicate that RNF121 participates in the quality control of NaV channels during their synthesis and subsequent transport to the membrane.
authors.affiliation: Center for Frontier Research, National Institute of Genetics, Mishima 411-8540, Japan; Department of Chemistry and Biological Science, School of Science and Engineering, Aoyama Gakuin University, Sagamihara 252-5258, Japan;
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Ogino
authors.affiliation: Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065;
authors.forename: Sean E
authors.initials: SE
authors.lastname: Low
authors.affiliation: Center for Frontier Research, National Institute of Genetics, Mishima 411-8540, Japan;
authors.forename: Kenta
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-1048;
authors.forename: Louis
authors.initials: L
authors.lastname: Saint-Amant
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-1048; Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109-5646;
authors.forename: Weibin
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Division of Molecular and Developmental Biology, National Institute of Genetics, Mishima 411-8540, Japan; Department of Genetics, Graduate University for Advanced Studies, Mishima 411-8540, Japan;
authors.forename: Akira
authors.initials: A
authors.lastname: Muto
authors.affiliation: Division of Molecular and Developmental Biology, National Institute of Genetics, Mishima 411-8540, Japan; Department of Genetics, Graduate University for Advanced Studies, Mishima 411-8540, Japan;
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Asakawa
authors.affiliation: Saitama University Brain Science Institute, Saitama 338-8570, Japan; and.
authors.forename: Junichi
authors.initials: J
authors.lastname: Nakai
authors.affiliation: Division of Molecular and Developmental Biology, National Institute of Genetics, Mishima 411-8540, Japan; Department of Genetics, Graduate University for Advanced Studies, Mishima 411-8540, Japan;
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-1048;
authors.forename: John Y
authors.initials: JY
authors.lastname: Kuwada
authors.affiliation: Center for Frontier Research, National Institute of Genetics, Mishima 411-8540, Japan; Department of Chemistry and Biological Science, School of Science and Engineering, Aoyama Gakuin University, Sagamihara 252-5258, Japan; Department of Genetics, Graduate University for Advanced Studies, Mishima 411-8540, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan hihirata@nig.ac.jp.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hirata
mesh_terms: D000818:Animals; D001483:Base Sequence; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D059748:Proteolysis; D054829:RING Finger Domains; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D061566:Voltage-Gated Sodium Channels / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D025801:Ubiquitin; D061566:Voltage-Gated Sodium Channels; D029961:Zebrafish Proteins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
keywords: escape; touch response; ubiquitin; voltage-gated sodium channel; zebrafish