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PMID: 18606142 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Neuraminidase 1 is a negative regulator of lysosomal exocytosis.

Developmental cell ·Vol. 15 ·No. 1 ·2008-07-00 ·Pages 74-86

Yogalingam G, Bonten EJ, van de Vlekkert D, Hu H, Moshiach S, Connell SA, d'Azzo A

Abstract

Lysosomal exocytosis is a Ca2+-regulated mechanism that involves proteins responsible for cytoskeletal attachment and fusion of lysosomes with the plasma membrane. However, whether luminal lysosomal enzymes contribute to this process remains unknown. Here we show that neuraminidase NEU1 negatively regulates lysosomal exocytosis in hematopoietic cells by processing the sialic acids on the lysosomal membrane protein LAMP-1. In macrophages from NEU1-deficient mice, a model of the disease sialidosis, and in patients' fibroblasts, oversialylated LAMP-1 enhances lysosomal exocytosis. Silencing of LAMP-1 reverts this phenotype by interfering with the docking of lysosomes at the plasma membrane. In neu1-/- mice the excessive exocytosis of serine proteases in the bone niche leads to inactivation of extracellular serpins, premature degradation of VCAM-1, and loss of bone marrow retention. Our findings uncover an unexpected mechanism influencing lysosomal exocytosis and argue that exacerbations of this process form the basis for certain genetic diseases.

MeSH Terms
Animals Bone Marrow Cells/cytology Cell Membrane/metabolism Cells, Cultured Disease Models, Animal Exocytosis Fibroblasts/physiology Gene Expression Regulation Humans Lysosomal-Associated Membrane Protein 1/metabolism Lysosomes/physiology Macrophages/physiology Mice Mice, Knockout Models, Biological Mucolipidoses/genetics,pathology Neuraminidase/genetics,metabolism Stem Cells/cytology,physiology Substrate Specificity
Chemicals
Lysosomal-Associated Membrane Protein 1 NEU1 protein, human Neu1 protein, mouse Neuraminidase
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Yogalingam Gouri
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
Bonten Erik J
van de Vlekkert Diantha
Hu Huimin
Moshiach Simon
Connell Samuel A
d'Azzo Alessandra
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Article Info
Journal
Developmental cell
Abbr.
Dev Cell
ISSN
1878-1551
DOI
10.1016/j.devcel.2008.05.005
Published
2008-07-00
Pages
74-86
Language
English
Region
United States
NLM ID
101120028
PMCID
PMC2664108
Subset
IM
Grants
NIGMS NIH HHS · GM60905 · United States
NIDDK NIH HHS · DK52025 · United States
NIGMS NIH HHS · R01 GM060950-07 · United States
NIDDK NIH HHS · R01 DK052025 · United States
NIGMS NIH HHS · R01 GM060950 · United States
External Links
PubMed source DOI: 10.1016/j.devcel.2008.05.005 PMC Full Text View journal details
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