title: Positive regulation of insulin signaling by neuraminidase 1.
abstract: 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 the 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, and 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.
authors.affiliation: Division of Medical Genetics, Sainte-Justine University Hospital Research Center, University of Montréal, Montréal, Québec, Canada.
authors.forename: Larbi
authors.initials: L
authors.lastname: Dridi
authors.forename: Volkan
authors.initials: V
authors.lastname: Seyrantepe
authors.forename: Anne
authors.initials: A
authors.lastname: Fougerat
authors.forename: Xuefang
authors.initials: X
authors.lastname: Pan
authors.forename: Eric
authors.initials: E
authors.lastname: Bonneil
authors.forename: Pierre
authors.initials: P
authors.lastname: Thibault
authors.forename: Allain
authors.initials: A
authors.lastname: Moreau
authors.forename: Grant A
authors.initials: GA
authors.lastname: Mitchell
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Heveker
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cairo
authors.forename: Tarik
authors.initials: T
authors.lastname: Issad
authors.forename: Alexander
authors.initials: A
authors.lastname: Hinek
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Pshezhetsky
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D005951:Glucose Tolerance Test; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009081:Mucolipidoses / Q000235:genetics / Q000378:metabolism*; D009439:Neuraminidase / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D007328:Insulin; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; C110128:Neu1 protein, mouse; D009439:Neuraminidase