Genetic analysis of the heparan modification network in Caenorhabditis elegans

Robert A. Townley, Hannes E. Buelow

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Heparan sulfates (HS) are highly modified sugar polymers in multicellular organisms that function in cell adhesion and cellular responses to protein signaling. Functionally distinct, cell type-dependent HS modification patterns arise as the result of a conserved network of enzymes that catalyze deacetylations, sulfations, and epimerizations in specific positions of the sugar residues. To understand the genetic interactions of the enzymes during the HS modification process, we have measured the composition of HS purified from mutant strains of Caenorhabditis elegans. From these measurements we have developed a genetic network model of HS modification. We find the interactions to be highly recursive positive feed-forward and negative feedback loops. Our genetic analyses show that the HS C-5 epimerase hse-5, the HS 2-O-sulfotransferase hst-2, or the HS 6-O-sulfo-transferase hst-6 inhibit N-sulfation. In contrast, hse-5 stimulates both 2-O- and 6-O-sulfation and, hst-2 and hst-6 inhibit 6-O- and 2-O-sulfation, respectively. The effects of hst-2 and hst-6 on N-sulfation, 6-O-sulfation, and 2-O-sulfation appear largely dependent on hse-5 function. This core of regulatory interactions is further modulated by 6-O-endosulfatase activity (sul-1). 47% of all 6-O-sulfates get removed from HS and this editing process is dependent on hst-2, thereby providing additional negative feedback between 2-O- and 6-O-sulfation. These findings suggest that the modification patterns are highly sensitive to the relative composition of the HS modification enzymes. Our comprehensive genetic analysis forms the basis of understanding the HS modification network in metazoans.

Original languageEnglish (US)
Pages (from-to)16824-16831
Number of pages8
JournalJournal of Biological Chemistry
Volume286
Issue number19
DOIs
StatePublished - May 13 2011

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Heparitin Sulfate
Caenorhabditis elegans
Sugars
Enzymes
Racemases and Epimerases
Feedback
Sulfotransferases
Genetic Models
Transferases
Cell adhesion
Cell Adhesion
Sulfates
Chemical analysis
Polymers

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Genetic analysis of the heparan modification network in Caenorhabditis elegans. / Townley, Robert A.; Buelow, Hannes E.

In: Journal of Biological Chemistry, Vol. 286, No. 19, 13.05.2011, p. 16824-16831.

Research output: Contribution to journalArticle

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