Compensatory expression of human N-acetylglucosaminyl-1-phosphotransferase subunits in mucolipidosis type III gamma.
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Compensatory expression of human N-acetylglucosaminyl-1-phosphotransferase subunits in mucolipidosis type III gamma. / Pohl, Sandra; Tiede, Stephan; Castrichini, Monica; Cantz, Michael; Gieselmann, Volkmar; Braulke, Thomas.
In: BBA-MOL BASIS DIS, Vol. 1792, No. 3, 3, 2009, p. 221-225.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Compensatory expression of human N-acetylglucosaminyl-1-phosphotransferase subunits in mucolipidosis type III gamma.
AU - Pohl, Sandra
AU - Tiede, Stephan
AU - Castrichini, Monica
AU - Cantz, Michael
AU - Gieselmann, Volkmar
AU - Braulke, Thomas
PY - 2009
Y1 - 2009
N2 - The N-Acetylglucosaminyl-1-phosphotransferase plays a key role in the generation of mannose 6-phosphate (M6P) recognition markersessential for efficient transport of lysosomal hydrolases to lysosomes. The phosphotransferase is composed of six subunits (alpha2, beta2, gamma2). The alpha- and beta-subunits are catalytically active and encoded by a single gene, GNPTAB, whereas the gamma-subunit encoded by GNPTG is proposed to recognize conformational structures common to lysosomal enzymes. Defects in GNPTG cause mucolipidosis type III gamma, which is characterized by missorting and cellular loss of lysosomal enzymes leading to lysosomal accumulation of storage material. Using plasmon resonance spectrometry, we showed that recombinant gamma-subunit failed to bind the lysosomal enzyme arylsulfatase A. Additionally, the overexpression of the gamma-subunit in COS7 cells did not result in hypersecretion of newly synthesized lysosomal enzymes expected for competition for binding sites of the endogenous phosphotransferase complex. Analysis of fibroblasts exhibiting a novel mutation in GNPTG (c.619insT, p.K207IfsX7) revealed that the expression of GNPTAB was increased whereas in gamma-subunit overexpressing cells the GNPTAB mRNA was reduced. The data suggest that the gamma-subunit is important for the balance of phosphotransferase subunits rather for general binding of lysosomal enzymes.
AB - The N-Acetylglucosaminyl-1-phosphotransferase plays a key role in the generation of mannose 6-phosphate (M6P) recognition markersessential for efficient transport of lysosomal hydrolases to lysosomes. The phosphotransferase is composed of six subunits (alpha2, beta2, gamma2). The alpha- and beta-subunits are catalytically active and encoded by a single gene, GNPTAB, whereas the gamma-subunit encoded by GNPTG is proposed to recognize conformational structures common to lysosomal enzymes. Defects in GNPTG cause mucolipidosis type III gamma, which is characterized by missorting and cellular loss of lysosomal enzymes leading to lysosomal accumulation of storage material. Using plasmon resonance spectrometry, we showed that recombinant gamma-subunit failed to bind the lysosomal enzyme arylsulfatase A. Additionally, the overexpression of the gamma-subunit in COS7 cells did not result in hypersecretion of newly synthesized lysosomal enzymes expected for competition for binding sites of the endogenous phosphotransferase complex. Analysis of fibroblasts exhibiting a novel mutation in GNPTG (c.619insT, p.K207IfsX7) revealed that the expression of GNPTAB was increased whereas in gamma-subunit overexpressing cells the GNPTAB mRNA was reduced. The data suggest that the gamma-subunit is important for the balance of phosphotransferase subunits rather for general binding of lysosomal enzymes.
KW - Animals
KW - Humans
KW - Male
KW - Child, Preschool
KW - COS Cells
KW - Cathepsin D metabolism
KW - Cercopithecus aethiops
KW - Cerebroside-Sulfatase metabolism
KW - DNA Mutational Analysis
KW - Mannosephosphates metabolism
KW - Mucolipidoses enzymology
KW - Mutation
KW - Recombinant Fusion Proteins genetics
KW - Transferases (Other Substituted Phosphate Groups) genetics
KW - Animals
KW - Humans
KW - Male
KW - Child, Preschool
KW - COS Cells
KW - Cathepsin D metabolism
KW - Cercopithecus aethiops
KW - Cerebroside-Sulfatase metabolism
KW - DNA Mutational Analysis
KW - Mannosephosphates metabolism
KW - Mucolipidoses enzymology
KW - Mutation
KW - Recombinant Fusion Proteins genetics
KW - Transferases (Other Substituted Phosphate Groups) genetics
M3 - SCORING: Zeitschriftenaufsatz
VL - 1792
SP - 221
EP - 225
JO - BBA-MOL BASIS DIS
JF - BBA-MOL BASIS DIS
SN - 0925-4439
IS - 3
M1 - 3
ER -
