Spatiotemporal Regulation of the NADP(H) Phosphatase Nocturnin


August 2021


Laothamatas, Isara

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Periodic changes in the environment are ubiquitous in the natural world. Among these, the most biologically relevant rhythm is the 24-hour geophysical day/night cycle. As an adaptive strategy, many organisms have evolved an endogenous biological clock to temporally organize their physiology and anticipate daily changes in the environment. At its core, the mammalian "circadian clock" is a molecular oscillator driven by a genetic transcription/translation feedback loop, which orchestrates the rhythmic expression of thousands of genes. An intimate link between circadian clocks and metabolism is established by the rhythmic transcription of output genes involved in almost every metabolic pathway. Among these oscillating genes, Nocturnin (also Noct; protein name: NOC) has one of the highest amplitude rhythms at the mRNA level. Mice with a loss-of-function in Noct possess metabolic phenotypes, where they are protected from high-fat diet-induced obesity and LPS-induced septic shock. However, the mechanism by which this occurs is not well-understood. Here, in collaboration with Green lab members and the Liou lab, I used both in vitro biochemical and in vivo cellular and mouse models to elucidate the molecular and physiological function of NOC. Even though NOC is highly-conserved with the endonuclease/exonuclease/phosphatase (EEP) domain-containing CCR4 family of deadenylases, we show that highly-purified recombinant NOC lacks ribonuclease activity. Instead, NOC catalyzes the dephosphorylation of NADP(H), and its activity level is associated with the cellular response to oxidative stress. Furthermore, we describe two isoforms of NOC and their spatiotemporal regulation in the mouse liver. Cytoplasmic NOC is constitutively-expressed throughout the day and associates externally with the endoplasmic reticulum and other membranes via N-terminal glycine myristoylation. In contrast, mitochondrial NOC levels are highly circadian with peak expression during the early dark phase. Overall, our work suggests that NOC links circadian clocks to metabolism by regulating local intracellular concentrations of NADP(H) in a manner that changes throughout the day.

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