Journal
JOURNAL OF CELL BIOLOGY
Volume 154, Issue 4, Pages 879-891Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200103132
Keywords
NADPH-oxidase; peroxidase; extracellular matrix; cuticle; dityrosine
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Funding
- NCI NIH HHS [R01 CA084138, CA84138] Funding Source: Medline
- NIAMS NIH HHS [AR/GM 44419] Funding Source: Medline
- NIDDK NIH HHS [T32 DK007298, DK 07298] Funding Source: Medline
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High molecular weight homologues of gp91 phox, the superoxide-generating subunit of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, have been identified in human (h) and Caenorhahditis elegans (Ce), and are termed Duox for dual oxidase because they have both a peroxidase homology domain and a gp91 phox domain. A topology model predicts that the enzyme will utilize cytosolic NADPH to generate reactive oxygen, but the function of the ecto peroxidase domain was unknown. Ce-Duox1 is expressed in hypodermal cells underlying the cuticle of larval animals. To investigate function, RNA interference (RNAi) was carried out in C. elegans. RNAi animals showed complex phenotypes similar to those described previously in mutations in collagen biosynthesis that are known to affect the cuticle, an extracellular matrix. Electron micrographs showed gross abnormalities in the cuticle of RNAi animals. In cuticle, collagen and other proteins are cross-linked via di- and trityrosine linkages, and these linkages were absent in RNAi animals. The expressed peroxidase domains of both Ce-Duox1 and h-Duox showed peroxidase activity and catalyzed crosslinking of free tyrosine ethyl ester. Thus, Ce-Duox catalyzes the cross-linking of tyrosine residues involved in the stabilization of cuticular extracellular matrix.
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