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© The Rockefeller University Press, 0021-9525/2001/8/879 $5.00
The Journal of Cell Biology, Volume 154, Number 4, August 20, 2001 879-892

Tyrosine cross-linking of extracellular matrix is catalyzed by Duox, a multidomain oxidase/peroxidase with homology to the phagocyte oxidase subunit gp91phox

¹ Department of Biochemistry, Emory University Medical School, Atlanta, GA 30322
² Department of Pathology, Emory University Medical School, Atlanta, GA 30322

Address correspondence to J. David Lambeth, Department of Biochemistry, Emory University Medical School, Atlanta, GA 30322. Tel.: (404) 727-5875. Fax: (404) 727-2738. E-mail: dlambe{at}bimcore.emory.edu

High molecular weight homologues of gp91phox, the superoxide-generating subunit of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, have been identified in human (h) and Caenorhabditis elegans (Ce), and are termed Duox for "dual oxidase" because they have both a peroxidase homology domain and a gp91phox 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 cross-linking of free tyrosine ethyl ester. Thus, Ce-Duox catalyzes the cross-linking of tyrosine residues involved in the stabilization of cuticular extracellular matrix.

Key Words: NADPH-oxidase; peroxidase; extracellular matrix; cuticle; dityrosine

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