Mice lacking mannose 6-phosphate uncovering enzyme activity have a milder phenotype than mice deficient for N-acetylglucosamine-1-phosphotransferase activity. Mol Biol Cell 2009 Oct;20(20):4381-9
Date
08/28/2009Pubmed ID
19710420Pubmed Central ID
PMC2762139DOI
10.1091/mbc.e09-05-0398Scopus ID
2-s2.0-70350094393 (requires institutional sign-in at Scopus site) 24 CitationsAbstract
The mannose 6-phosphate (Man-6-P) lysosomal targeting signal on acid hydrolases is synthesized by the sequential action of uridine 5'-diphosphate-N-acetylglucosamine: lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase) and GlcNAc-1-phosphodiester alpha-N-acetylglucosaminidase ("uncovering enzyme" or UCE). Mutations in the two genes that encode GlcNAc-1-phosphotransferase give rise to lysosomal storage diseases (mucolipidosis type II and III), whereas no pathological conditions have been associated with the loss of UCE activity. To analyze the consequences of UCE deficiency, the UCE gene was inactivated via insertional mutagenesis in mice. The UCE -/- mice were viable, grew normally and lacked detectable histologic abnormalities. However, the plasma levels of six acid hydrolases were elevated 1.6- to 5.4-fold over wild-type levels. These values underestimate the degree of hydrolase hypersecretion as these enzymes were rapidly cleared from the plasma by the mannose receptor. The secreted hydrolases contained GlcNAc-P-Man diesters, exhibited a decreased affinity for the cation-independent mannose 6-phosphate receptor and failed to bind to the cation-dependent mannose 6-phosphate receptor. These data demonstrate that UCE accounts for all the uncovering activity in the Golgi. We propose that in the absence of UCE, the weak binding of the acid hydrolases to the cation-independent mannose 6-phosphate receptor allows sufficient sorting to lysosomes to prevent the tissue abnormalities seen with GlcNAc-1-phosphotranferase deficiency.
Author List
Boonen M, Vogel P, Platt KA, Dahms N, Kornfeld SAuthor
Nancy M. Dahms PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBrain
Cathepsin D
Endocytosis
Female
Fibroblasts
Glycosylation
Golgi Apparatus
Hydrolases
Liver
Lysosomes
Male
Mannosephosphates
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutagenesis, Insertional
Phenotype
Phosphoric Diester Hydrolases
Protein Processing, Post-Translational
Receptor, IGF Type 2
Transferases (Other Substituted Phosphate Groups)
