PI3K Interplays between the Circadian Clock and Nutrient-Sensing Signaling Pathways

Coordination between the circadian clock and nutrient-sensing signaling pathways is physiologically “wired in” to anticipate and counter metabolic stress due to alterations in nutrient availability. The mammalian central clock in the suprachiasmatic nuclei of the hypothalamus meshes the peripheral clocks of different organs through neural and humoral signals. Nevertheless, the essential molecular players mediating this alignment of circadian clock metabolic rhythmicity and nutrient-sensing signaling pathways remain largely unidentified.

Alkhoury et al. now make a major contribution to our mechanistic understanding of this coordination by describing the unexpected role of class 3 phosphatidylinositol-3-kinase (PI3K), a Vps34/Vps15 complex that is the major source of the second messenger PI3P, in this interplay. The authors report that nuclear class 3 PI3K acts as a coactivator of the heterodimeric circadian driver Bmal1-Clock, in addition to its well-known pro-catabolic role in regulating endocytic trafficking and autophagy (1). Though both the lipid kinase Vps34 and the regulatory Vps15 subunits are able to interact and co-localize with RNA polymerase II, Alkhoury et al. show non-redundancy by knockout assay (1). Interestingly, the researchers found that Vps15 coactivates Bmal1-Clock separately from the Vps34-Vps15 complex, revealing a kinase-independent role of class 3 PI3K in clock control for metabolic rhythmicity in mouse liver. In addition, Vps15 acts as a transcriptional activator of the Ppat gene, which is involved in inosine monophosphate production and therefore pro-anabolic de novo purine nucleotide synthesis. These intriguing findings suggest how the circadian clock and nutrient-sensing signaling pathways are aligned through the actions of nuclear class 3 PI3K, and establish a basis for further interrogation of its nuclear transport, chromatin interactions, and nuclear interactome (1).

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