Cited by 69Proteoglycans and glycosaminoglycans researchLysosomal Storage Disorders ResearchOsteoarthritis Treatment and Mechanisms

A role for a lithium-inhibited Golgi nucleotidase in skeletal development and sulfation

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Frederick, Joshua P., Tafari, A. Tsahai, Wu, Sheue-Mei, Megosh, Louis C., Chiou, Shean-Tai, Irving, Ryan P., York, John D.·2008·Proceedings of the National Academy of Sciences

Abstract

Sulfation is an important biological process that modulates the function of numerous molecules. It is directly mediated by cytosolic and Golgi sulfotransferases, which use 3′-phosphoadenosine 5′-phosphosulfate to produce sulfated acceptors and 3′-phosphoadenosine 5′-phosphate (PAP). Here, we identify a Golgi-resident PAP 3′-phosphatase (gPAPP) and demonstrate that its activity is potently inhibited by lithium in vitro . The inactivation of gPAPP in mice led to neonatal lethality, lung abnormalities resembling atelectasis, and dwarfism characterized by aberrant cartilage morphology. The phenotypic similarities of gPAPP mutant mice to chondrodysplastic models harboring mutations within components of the sulfation pathway lead to the discovery of undersulfated chondroitin in the absence of functional enzyme. Additionally, we observed loss of gPAPP leads to perturbations in the levels of heparan sulfate species in lung tissue and whole embryos. Our data are consistent with a model that clearance of the nucleotide product of sulfotransferases within the Golgi plays an important role in glycosaminoglycan sulfation, provide a unique genetic basis for chondrodysplasia, and define a function for gPAPP in the formation of skeletal elements derived through endochondral ossification.

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  1. Kusche-Gullberg M, Kjellen L (2003) Sulfotransferases in glycosaminoglycan biosyn- thesis. Curr Opin Struct Biol 13:605-611.

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Authors
Frederick, J. P., Tafari, A. T., Wu, S.-M., Megosh, L. C., Chiou, S.-T., Irving, R. P., & York, J. D.
Affiliations
Howard Hughes Medical Institute (US)
Corresponding author
York, John D.
Venue
Proceedings of the National Academy of Sciences
Published
2008-08-19
Volume
105
Issue
33
Pages
11605-11612
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2038088062
Cited by
67
References
60
Citations by year
2026: 3 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 7 · 2020: 7 · 2019: 5 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 5 · 2014: 2 · 2013: 2 · 2012: 5
FWCI
2.04
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (R01‐grant)
  • University of California, San Diego
  • National Heart, Lung, and Blood Institute (R01 HL-55672, R01HL055672)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
Keywords
lithium inhibition, sulfation, sulfotransferase, 3'-phosphoadenosine 5'-phosphate, heparan sulfate, chondrodysplasia, skeletal development, endochondral ossification, atelectasis, dwarfism, glycosaminoglycan sulfation, Golgi apparatus
MeSH terms
Animals, Animals, Newborn, Bone and Bones, Cartilage, Cells, Cultured, Chondrodysplasia Punctata, Chondroitin, Embryo, Nonmammalian, Enzyme Inhibitors, Golgi Apparatus, Growth Plate, Heparitin Sulfate, Heparan Sulfate, Lithium, Male, Mice, Transgenic, Nucleotidases, Phylogeny, Sulfur, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Developmental, Body Patterning, Mice

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