Abstract
Reactive oxygen species (ROS) are toxic but essential molecules responsible for host defense and cellular signaling. Conserved NADPH oxidase (NOX) family enzymes direct the regulated production of ROS. Hydrogen peroxide (H2O2) generated by dual oxidases (DUOXs), a member of the NOX family, is crucial for innate mucosal immunity. In addition, H2O2 is required for cellular signaling mediated by protein modifications, such as the thyroid hormone biosynthetic pathway in mammals. In contrast to other NOX isozymes, the regulatory mechanisms of DUOX activity are less understood. Using Caenorhabditis elegans as a model, we demonstrate that the tetraspanin protein is required for induction of the DUOX signaling pathway in conjunction with the dual oxidase maturation factor (DUOXA). In the current study, we show that genetic mutation of DUOX (bli-3), DUOXA (doxa-1), and peroxidase (mlt-7) in C. elegans causes the same defects as a tetraspanin tsp-15 mutant, represented by exoskeletal deficiencies due to the failure of tyrosine cross-linking of collagen. The deficiency in the tsp-15 mutant was restored by co-expression of bli-3 and doxa-1, indicating the involvement of tsp-15 in the generation of ROS. H2O2 generation by BLI-3 was completely dependent on TSP-15 when reconstituted in mammalian cells. We also demonstrated that TSP-15, BLI-3, and DOXA-1 form complexes in vitro and in vivo. Cell-fusion-based analysis suggested that association with TSP-15 at the cell surface is crucial for BLI-3 activation to release H2O2. This study provides the first evidence for an essential role of tetraspanin in ROS generation.
Highlights
Reactive oxygen species (ROS) are considered deleterious byproducts of aerobic metabolism that inflict oxidative damage in organisms, and have been associated with numerous diseases and aging
In C. elegans, BLI-3 encodes a nematode orthologue of dual oxidases (DUOXs) that is essential for exoskeletal development via tyrosine cross-linking [17,25,26,27], but which functions in pathogeninduced ROS production [28,29,30]
ROS are essential for innate host defense and multiple physiological processes and are generated by conserved NADPH oxidase (NOX) family enzymes
Summary
Reactive oxygen species (ROS) are considered deleterious byproducts of aerobic metabolism that inflict oxidative damage in organisms, and have been associated with numerous diseases and aging. The physiological generation of ROS is directed by the NADPH oxidase (NOX) family of enzymes, which are highly conserved integral membrane proteins comprising seven members in mammals (NOX1–NOX5, DUOX1, and DUOX2) [3,4,5]. Studies of the NOX family have uncovered multiple biological functions of ROS in developmental processes, apoptosis, protein modification, cellular signaling and are well documented in host defense mechanisms [1,6,7,8]. In C. elegans, BLI-3 encodes a nematode orthologue of DUOXs that is essential for exoskeletal development via tyrosine cross-linking [17,25,26,27], but which functions in pathogeninduced ROS production [28,29,30]
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