Nox enzymes from fungus to fly to fish and what they tell us about Nox function in mammals

Abstract

The production of reactive oxygen species (ROS) in a highly regulated fashion is a hallmark of members of the NADPH oxidase (Nox) family of enzymes. Nox enzymes are present in most eukaryotic groups such as the amebozoid, fungi, algae and plants, and animals, in which they are involved in seemingly diverse biological processes. However, a comprehensive survey of Nox functions throughout biology reveals common functional themes. Noxes are often activated in response to stressful conditions such as nutrient starvation, physical damage, or pathogen attack. Although the end result varies depending on the organism and tissue, Nox-produced ROS mediate the response to the adverse stimuli, such as innate immunity responses in plants and animals or cell differentiation in Dictyostelium, fungi, and plants. These responses involve ROS-mediated signaling mechanisms occurring at intracellular or cell-to-cell levels and sometimes involve cell wall or extracellular matrix cross-linking. Indeed, Noxes are involved in local and systemic signaling from plants to fish and in cross-linking of the plant hair-cell wall, synthesis of the nematode cuticle, and formation of the sea urchin fertilization envelope. The extensive use of Nox enzymes in biology to regulate cell-to-cell signaling and morphogenesis suggests that additional functions in mammalian signaling and development remain to be discovered.

Fig. 1

Regulation and Defining Features of Human Nox/Duox Homologues

Fig. 2. Local and Systemic Cell-to-Cell Signaling by Nox Enzymes in Plant and Fish in Response to Cell or Tissue Damage

The left panel depicts systemic signaling by RbohD-catalyzed production of ROS in plants. According to this model, cell damage initiates activation of RbohD at the wound site, and the signal is then propagated systemically by ROS-induced activation of RbohD (indicated by white boxes) in neighboring cells, so that diffusion does not diminish the concentration of ROS. The right-hand panel depicts H₂O₂ signaling in fish in response to wounding, which activates the calcium-dependent Duox (indicated by small white boxes), resulting in a gradient of H₂O₂ around the wound site. H₂O₂ then acts both directly to sterilize the area around the wound, and as a chemotactic factor to recruit neutrophils to the region.

Figure 3. Universality of tyrosine cross-linking among diverse phyla

Shown are examples of tyrosine cross-linking in diverse organisms including nematodes, sea urchin eggs, and plants. The reaction requires H₂O₂ and a peroxidase, which may be either part of a Duox enzyme or may be a separately encoded peroxidase (Px). Also shown in plants is the distribution of ROS (reactive oxygen species) and protons in growing versus quiescent root hairs.

Fig. 4. Biological roles for ROS-generating and Peroxidase-like domains of C. elegans Duox1

Duox in nematode worms functions in both gastrointestinal immunity and in cuticle stabilization, the latter via tyrosine cross-linking as shown in Fig. 3. Various domains and prosthetic groups are indicated, including the peroxidase-homology domain, which contains a heme group (square with dark center). A point mutation in the peroxidase domain inactivates the cuticle stabilization (producing the blister phenotype), but does not affect GI immunity, indicating that the immunity function does not require a functional peroxidase domain.