Positive Regulation of Insulin Signaling by Neuraminidase 1
- Larbi Dridi1,
- Volkan Seyrantepe1,
- Anne Fougerat1,
- Xuefang Pan1,
- Éric Bonneil2,
- Pierre Thibault2,
- Allain Moreau3,4,
- Grant A. Mitchell1,
- Nikolaus Heveker4,
- Christopher W. Cairo5,
- Tarik Issad6,7,
- Alexander Hinek8 and
- Alexey V. Pshezhetsky1,4,9
- 1Division of Medical Genetics and 3Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Sainte-Justine University Hospital Research Center, University of Montreal, Montréal, Canada
- 2Institute of Research in Immunology and Cancer, University of Montréal, Montréal, Canada
- 3Department of Stomatology, Faculty of Dentistry, University of Montréal, Montréal, Canada
- 4Department of Biochemistry, University of Montréal, Montréal, Québec, Canada
- 5Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada
- 6Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France
- 7INSERM, U1016, Paris, France
- 8Physiology and Experimental Medicine Program, The Hospital for Sick Children, University of Toronto, Ontario, Canada
- 9Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Montréal, Canada
- *Corresponding Author: Alexey V. Pshezhetsky; E-mail:
Neuraminidases (sialidases) catalyze the removal of sialic acid residues from sialylated glycoconjugates. We now report that mammalian neuraminidase 1 (Neu1), in addition to its catabolic function in lysosomes, is transported to the cell surface where it is involved in regulation of insulin signaling. Insulin binding to its receptor rapidly induces interaction of the receptor with Neu1, which hydrolyzes sialic acid residues in the glycan chains of the receptor and, consequently, induces its activation. Cells from sialidosis patients with a genetic deficiency of Neu1 show impairment of insulin-induced phosphorylation of downstream protein kinase AKT, while treatment of these cells with purified Neu1 restores signaling. Genetically-modified mice with ∼10% of the normal Neu1 activity exposed to a high-fat diet develop hyperglycemia and insulin resistance twice as fast as their wild type counterparts. Together, these studies identify Neu1 as a novel component of the signaling pathways of energy metabolism and glucose uptake.
- Received December 24, 2012.
- Accepted March 18, 2013.
- © 2013 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.