Structure, regulation, and physiological functions of NADPH oxidase 5 (NOX5)

Abstract

NOX5 is the last member of the NADPH oxidase (NOXs) family to be identified and presents some specific characteristics differing from the rest of the NOXs. It contains four Ca²⁺ binding domains at the N-terminus and its activity is regulated by the intracellular concentration of Ca²⁺. NOX5 generates superoxide (O₂^•-) using NADPH as a substrate, and it modulates functions related to processes in which reactive oxygen species (ROS) are involved. Those functions appear to be detrimental or beneficial depending on the level of ROS produced. For example, the increase in NOX5 activity is related to the development of various oxidative stress-related pathologies such as cancer, cardiovascular, and renal diseases. In this context, pancreatic expression of NOX5 can negatively alter insulin action in high-fat diet-fed transgenic mice. This is consistent with the idea that the expression of NOX5 tends to increase in response to a stimulus or a stressful situation, generally causing a worsening of the pathology. On the other hand, it has also been suggested that it might have a positive role in preparing the body for metabolic stress, for example, by inducing a protective adipose tissue adaptation to the excess of nutrients supplied by a high-fat diet. In this line, its endothelial overexpression can delay lipid accumulation and insulin resistance development in obese transgenic mice by inducing the secretion of IL-6 followed by the expression of thermogenic and lipolytic genes. However, as NOX5 gene is not present in rodents and human NOX5 protein has not been crystallized, its function is still poorly characterized and further extensive research is required.

Keywords: Inflammation; Insulin resistance; NADPH oxidase; NOX; Obesity; Oxidative stress.

Fig. 1

Schematic representation of the structure of the different NOXs. A Structure of isoforms 1–3. B Structure of isoform 4. C Structure of isoform 5. D Structure of DUOX1-2 isoforms. The transmembrane domains (blue), the subunits necessary for the activation of each enzyme (brown), the stabilizer subunits (orange), and maturation factors in DUOX (red) and the FAD/NADH binding domains (purple) are indicated in each figure. Image adapted from Buvelot et al. [17]

Fig. 2

Schematic representation of the structure of NOX5. The protein contains six transmembrane domains (dark blue), with the N- and C-terminus disposed toward the cytosol. At the amino end, the EF-hand motifs are located, capable of binding Ca²⁺ ions (golden). The FAD domain (yellow) and the NADPH binding motif (purple), responsible for the production of O₂.^•−, and the polybasic domain (PBR-C) (pale blue) are located at the carboxyl end. Image adapted from Touyz et al. [103]

Fig. 3

Schematic representation of the structure of the six NOX5 variants. The transmembrane domains and the C-terminus are identical for all isoforms. The main differences are present at the amino end. Image adapted from Fulton et al. [35]

Fig. 4

Schematic representation of the main physiological and physiopathological functions described so far for NOX5