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Selenoprotein Gene Nomenclature*

Open AccessPublished:September 19, 2016DOI:https://doi.org/10.1074/jbc.M116.756155
      The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4, and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine sulfoxide reductase B1), and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15-kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV), and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing, and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates.

      Introduction

      Selenium is an essential trace element in humans, which is present in proteins in the form of the 21st proteinogenic amino acid, selenocysteine (Sec).
      The abbreviations used are: Sec, selenocysteine; TXNRD, thioredoxin reductases; GPX, glutathione peroxidase; DIO, iodothyronine deiodinase; SEPHS2, selenophosphate synthetase 2; SELENOF, 15-kDa selenoprotein; SELENOH, selenoprotein H; SELENOI, selenoprotein I; SELENOK, selenoprotein K; SELENOM, selenoprotein M; SELENON, selenoprotein N; SELENOO, selenoprotein O; SELENOP, selenoprotein P; SELENOS, selenoprotein S; SELENOT, selenoprotein T; SELENOV, selenoprotein V; SELENOW, selenoprotein W; HGNC, HUGO Gene Nomenclature Committee.
      Sec is co-translationally inserted into a polypeptide chain in response to in-frame UGA codons directed by the Sec insertion sequence element, a stem-loop structure in the 3′-UTRs of selenoprotein mRNAs. The human genome contains 25 selenoprotein genes (
      • Kryukov G.V.
      • Castellano S.
      • Novoselov S.V.
      • Lobanov A.V.
      • Zehtab O.
      • Guigó R.
      • Gladyshev V.N.
      Characterization of mammalian selenoproteomes.
      ), and selenoproteins are essential for embryo development and human health (
      • Bösl M.R.
      • Takaku K.
      • Oshima M.
      • Nishimura S.
      • Taketo M.M.
      Early embryonic lethality caused by targeted disruption of the mouse selenocysteine tRNA gene (Trsp).
      ,
      • Schweizer U.
      • Fradejas-Villar N.
      Why 21? the significance of selenoproteins for human health revealed by inborn errors of metabolism.
      ). Among the selenoproteins, 13 have known functions; at least 12 of them serve as oxidoreductases, wherein Sec is the catalytic redox-active residue. The redox theme is also common for selenoproteins in other organisms (
      • Fomenko D.E.
      • Xing W.
      • Adair B.M.
      • Thomas D.J.
      • Gladyshev V.N.
      High-throughput identification of catalytic redox-active cysteine residues.
      ).
      The remaining 12 selenoproteins either have no known function, or their functions are only partially established. One of the selenoproteins, selenoprotein P (
      • Burk R.F.
      • Hill K.E.
      Regulation of selenium metabolism and transport.
      ), requires special mention as it has more than one Sec. It is a major plasma selenoprotein that delivers selenium primarily from the liver to other organs (
      • Carlson B.A.
      • Novoselov S.V.
      • Kumaraswamy E.
      • Lee B.J.
      • Anver M.R.
      • Gladyshev V.N.
      • Hatfield D.L.
      Specific excision of the selenocysteine tRNA[Ser]Sec (Trsp) gene in mouse liver demonstrates an essential role of selenoproteins in liver function.
      ,
      • Schomburg L.
      • Schweizer U.
      • Holtmann B.
      • Flohé L.
      • Sendtner M.
      • Köhrle J.
      Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues.
      ), and is involved in selenium transport and metabolism within organs. However, this protein also has an N-terminal Sec-containing thioredoxin domain similar to that found in most selenoproteins with known functions, which points to a potential redox function. Several other selenoproteins, including selenoproteins H, M, T, V, W, and Sep15, also possess thioredoxin-like domains, suggesting redox-related functions (
      • Dikiy A.
      • Novoselov S.V.
      • Fomenko D.E.
      • Sengupta A.
      • Carlson B.A.
      • Cerny R.L.
      • Ginalski K.
      • Grishin N.V.
      • Hatfield D.L.
      • Gladyshev V.N.
      SelT, SelW, SelH, and Rdx12: genomics and molecular insights into the functions of selenoproteins of a novel thioredoxin-like family.
      ).
      Selenoproteins are not all homologous, but are characterized by their incorporation of Sec. Historically they have been given designations by the groups that discovered them, e.g. because of its presence in plasma the respective selenoprotein was named selenoprotein P (
      • Motsenbocker M.A.
      • Tappel A.L.
      A selenocysteine-containing selenium-transport protein in rat plasma.
      ,
      • Burk R.F.
      • Gregory P.E.
      Some characteristics of 75Se-P, a selenoprotein found in rat liver and plasma, and comparisons of it with selenoglutathione peroxidase.
      ), or because of its size another protein was called the 15-kDa selenoprotein or Sep15 (
      • Gladyshev V.N.
      • Jeang K.T.
      • Wootton J.C.
      • Hatfield D.L.
      A new human selenium-containing protein. Purification, characterization, and cDNA sequence.
      ). However, some selenoproteins were identified independently by two or more groups, which created confusion and discrepancies in the field. For example, the same protein was named selenoprotein R by one group (
      • Kryukov G.V.
      • Kryukov V.M.
      • Gladyshev V.N.
      New mammalian selenocysteine-containing proteins identified with an algorithm that searches for selenocysteine insertion sequence elements.
      ), but discovered concurrently and designated by another group as selenoprotein X (
      • Lescure A.
      • Gautheret D.
      • Carbon P.
      • Krol A.
      Novel selenoproteins identified in silico and in vivo by using a conserved RNA structural motif.
      ). This protein was then functionally characterized (
      • Kryukov G.V.
      • Kumar R.A.
      • Koc A.
      • Sun Z.
      • Gladyshev V.N.
      Selenoprotein R is a zinc-containing stereo-specific methionine sulfoxide reductase.
      ) and renamed MsrB1 (for methionine-R-sulfoxide reductase 1) (
      • Kim H.Y.
      • Gladyshev V.N.
      Methionine sulfoxide reduction in mammals: characterization of methionine-R-sulfoxide reductases.
      ), but all three designations persist in the literature and/or databases. Another problematic example is the nomenclature used for thioredoxin reductases. The names for the first thioredoxin reductase, which had been known decades before its selenoprotein nature was discovered (
      • Holmgren A.
      Bovine thioredoxin system: purification of thioredoxin reductase from calf liver and thymus and studies of its function in disulfide reduction.
      ), are generally internally consistent, although they differ in the abbreviations used, e.g. TR1 and TrxR1 (
      • Arnér E.S.
      • Holmgren A.
      Physiological functions of thioredoxin and thioredoxin reductase.
      ). The second and third thioredoxin reductases discovered, however, were named inconsistently by the authors, wherein the mitochondrial thioredoxin reductase was designated as TrxR2 (
      • Lee S.R.
      • Kim J.R.
      • Kwon K.S.
      • Yoon H.W.
      • Levine R.L.
      • Ginsburg A.
      • Rhee S.G.
      Molecular cloning and characterization of a mitochondrial selenocysteine-containing thioredoxin reductase from rat liver.
      ) and TR3 (
      • Sun Q.A.
      • Wu Y.
      • Zappacosta F.
      • Jeang K.T.
      • Lee B.J.
      • Hatfield D.L.
      • Gladyshev V.N.
      Redox regulation of cell signaling by selenocysteine in mammalian thioredoxin reductases.
      ), and the testis-specific thioredoxin-glutathione reductase has been alternatively labeled as TR2 (
      • Sun Q.A.
      • Wu Y.
      • Zappacosta F.
      • Jeang K.T.
      • Lee B.J.
      • Hatfield D.L.
      • Gladyshev V.N.
      Redox regulation of cell signaling by selenocysteine in mammalian thioredoxin reductases.
      ), TrxR3, or TGR.
      Designations are also confusing for several other selenoproteins. For example, selenoprotein S was named SelS (
      • Kryukov G.V.
      • Castellano S.
      • Novoselov S.V.
      • Lobanov A.V.
      • Zehtab O.
      • Guigó R.
      • Gladyshev V.N.
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      ), but a later paper introduced the designation VIMP (
      • Ye Y.
      • Shibata Y.
      • Yun C.
      • Ron D.
      • Rapoport T.A.
      A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol.
      ). Similarly, selenoprotein H was named SelH (
      • Kryukov G.V.
      • Castellano S.
      • Novoselov S.V.
      • Lobanov A.V.
      • Zehtab O.
      • Guigó R.
      • Gladyshev V.N.
      Characterization of mammalian selenoproteomes.
      ), but also C11orf31, and selenoprotein I was named SelI (
      • Kryukov G.V.
      • Castellano S.
      • Novoselov S.V.
      • Lobanov A.V.
      • Zehtab O.
      • Guigó R.
      • Gladyshev V.N.
      Characterization of mammalian selenoproteomes.
      ), but also called EPT1 (
      • Horibata Y.
      • Hirabayashi Y.
      Identification and characterization of human ethanolaminephosphotransferase1.
      ). To avoid confusion, and at the instigation of the HUGO Gene Nomenclature Committee (HGNC), we describe a new standardized designation system for human (and other vertebrate) selenoproteins.

      Author Contributions

      The article was drafted by V. N. G. in consultation with other authors. All authors contributed to revisions and discussion.

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