Oxidative activation of type III CD38 by NADPH oxidase-derived hydrogen peroxide in Ca²⁺ signaling

Reactive oxygen species (ROS) derived from NADPH oxidase (Nox) has been shown to activate ADP-ribosyl cyclase (ARC), which produces the Ca²⁺ mobilizing second messenger, cyclic ADP-ribose (cADPR). In the present study, we examined how ROS activates cluster of differentiation (CD)38, a mammalian prototype of ARC. CD38 exists in type II and III forms with opposing membrane orientation. This study showed the coexpression of type II and III CD38 in lymphokine-activated killer (LAK) cells. The catalytic site of the constitutively active type II CD38 faces the outside of the cell or the inside of early endosomes (EEs), whereas the basally inactive type III CD38 faces the cytosol. Type III CD38 interacted with Nox4/phosphorylated-p22phox (p-p22phox) in EEs of LAK cells upon IL-8 treatment. H₂O₂ derived from Nox4 activated type III CD38 by forming a disulfide bond between Cys164 and Cys177, resulting in increased cADPR formation. Our study identified the mechanism by which type III CD38 is activated in an immune cell (LAK), in which H₂O₂ generated by Nox4 oxidizes and activates type III CD38 to generate cADPR. These findings provide a novel model of cross-talk between ROS and Ca²⁺ signaling.-Park, D.-R., Nam, T.-S., Kim, Y.-W., Bae, Y. S., Kim, U.-H. Oxidative activation of type III CD38 by NADPH oxidase-derived hydrogen peroxide in Ca²⁺ signaling.