Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea.
National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University Medical School, Jeonju, Korea.
FASEB J. 2019 Mar;33(3):3404-3419. doi: 10.1096/fj.201800235R. Epub 2018 Nov 19.
Reactive oxygen species (ROS) derived from NADPH oxidase (Nox) has been shown to activate ADP-ribosyl cyclase (ARC), which produces the Ca 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. HO 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 HO generated by Nox4 oxidizes and activates type III CD38 to generate cADPR. These findings provide a novel model of cross-talk between ROS and Ca 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 Ca signaling.
活性氧（ROS）来源于 NADPH 氧化酶（Nox），已被证明可以激活 ADP-核糖基环化酶（ARC），产生钙动员第二信使环 ADP-核糖（cADPR）。在本研究中，我们研究了 ROS 如何激活 CD38，它是 ARC 的哺乳动物原型。CD38 有 II 型和 III 型两种形式，具有相反的膜定向。这项研究表明，淋巴因子激活的杀伤（LAK）细胞共表达 II 型和 III 型 CD38。组成型激活的 II 型 CD38 的催化位点面向细胞外或早期内体（EEs）的内部，而基础失活的 III 型 CD38 面向细胞质。III 型 CD38 在 LAK 细胞的 EE 中与 Nox4/磷酸化-p22phox（p-p22phox）相互作用，在 IL-8 处理后。Nox4 产生的 HO 通过在 Cys164 和 Cys177 之间形成二硫键来激活 III 型 CD38，从而增加 cADPR 的形成。我们的研究确定了 Nox4 产生的 HO 氧化并激活 III 型 CD38 以产生 cADPR 的免疫细胞（LAK）中 III 型 CD38 被激活的机制。这些发现提供了一个新的 ROS 和 Ca 信号转导之间相互作用的模型。
