Casein kinase 1 gamma regulates oxidative stress response via interacting with the NADPH dual oxidase complex.

Oxidative stress response is a fundamental biological process mediated by conserved mechanisms. The identities and functions of some key regulators remain unknown. Here, we report a novel role of C. elegans casein kinase 1 gamma CSNK-1 (also known as CK1γ or CSNK1G) in regulating oxidative stress response and ROS levels. csnk-1 interacted with the bli-3/tsp-15/doxa-1 NADPH dual oxidase genes via genetic nonallelic noncomplementation to affect C. elegans survival in oxidative stress. The genetic interaction was supported by specific biochemical interactions between DOXA-1 and CSNK-1 and potentially between their human orthologs DUOXA2 and CSNK1G2. Consistently, CSNK-1 was required for normal ROS levels in C. elegans. CSNK1G2 and DUOXA2 each can promote ROS levels in human cells, effects that were suppressed by a small molecule casein kinase 1 inhibitor. We also detected genetic interactions between csnk-1 and skn-1 Nrf2 in oxidative stress response. Together, we propose that CSNK-1 CSNK1G defines a novel conserved regulatory mechanism for ROS homeostasis. Author summary: Oxidative stress response is a fundamental life process that regulates the generation and elimination of reactive oxygen species (ROS) and manages ROS-elicited damages. Some key regulatory mechanisms remain to be elucidated. While analyzing mutations promoting the survival of the nematode Caenorhabditis elegans in excess iodide, an oxidative stressor, we identified the casein kinase 1 gamma gene csnk-1. Casein kinase 1 gamma proteins are highly conserved and proposed to have important biomedical functions. However, they are understudied and their effects on oxidative stress response are unknown. We combined genetic, biochemical and cell biology approaches to show that casein kinase 1 gamma members in C. elegans and humans are novel regulators of oxidative stress response and promoters of ROS levels. These activities involve interactions with the NADPH dual oxidase complex, which are likely mediated by physical interactions between casein kinase 1 gamma and the dual oxidase maturation factor. Our findings provide new mechanistic insights into the regulation of ROS homeostasis and uncover an important function of the "dark" casein kinase 1 gamma. [ABSTRACT FROM AUTHOR]