title: Localization of UDP-GlcNAc 2-epimerase/ManAc kinase (GNE) in the Golgi complex and the nucleus of mammalian cells.
abstract: The bifunctional enzyme UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) is essential for early embryonic development and catalyzes the rate limiting step in sialic acid biosynthesis. Although epimerase and kinase activities have been attributed to GNE, little is known about the regulation, differential expression, and subcellular localization of GNE in vivo. Mutations in GNE cause a rare inherited muscle disorder in humans called hereditary inclusion body myopathy (HIBM). However, the role of GNE in HIBM pathogenesis has not been defined yet. Here, we show that the GNE protein is expressed in various mammalian cells and tissues with highest levels found in cancer cells and liver. In human skeletal muscle, GNE protein is developmentally regulated: high levels are found in immature myoblasts but low levels in mature skeletal muscle. The GNE protein colocalizes with resident proteins of the Golgi compartment in a variety of human cells including muscle. Drug-induced disruption of the Golgi and subsequent recovery reveals co-distribution of GNE along with Golgi-targeted proteins. This subcellular localization of GNE is in good agreement with its established role as the key enzyme of sialic acid biosynthesis, since the sialylation of glycoconjugates takes place in the Golgi complex. Surprisingly, GNE is also detected in the nucleus. Upon nocodazole treatment, GNE redistributes to the cytoplasm suggesting that GNE may act as a nucleocytoplasmic shuttling protein. A regulatory role for GNE shifting between the nuclear and the Golgi compartment is proposed. Further insight into GNE regulation may promote the understanding of HIBM pathogenesis.
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology and Gene Center, Ludwig-Maximilians-University, Genzentrum München, Feodor-Lynen-Str. 25, 81377 München, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Krause
authors.forename: Stephan
authors.initials: S
authors.lastname: Hinderlich
authors.forename: Shira
authors.initials: S
authors.lastname: Amsili
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Horstkorte
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.forename: Zohar
authors.initials: Z
authors.lastname: Argov
authors.forename: Stella
authors.initials: S
authors.lastname: Mitrani-Rosenbaum
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D020126:Brefeldin A / Q000494:pharmacology; D002451:Cell Compartmentation / Q000502:physiology; D002467:Cell Nucleus / Q000201:enzymology*; D003593:Cytoplasm / Q000201:enzymology; D006001:Glycoconjugates / Q000096:biosynthesis*; D006056:Golgi Apparatus / Q000201:enzymology*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000254:growth & development; D032446:Myoblasts / Q000201:enzymology; D018979:Myositis, Inclusion Body / Q000151:congenital / Q000201:enzymology; D019158:N-Acetylneuraminic Acid / Q000096:biosynthesis*; D009369:Neoplasms / Q000201:enzymology / Q000503:physiopathology; D015739:Nocodazole / Q000494:pharmacology; D039904:Pluripotent Stem Cells; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D006001:Glycoconjugates; D009097:Multienzyme Complexes; D011500:Protein Synthesis Inhibitors; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase; D020126:Brefeldin A; D019158:N-Acetylneuraminic Acid; D015739:Nocodazole