bims-ciryme 2023-04-16 papers

Issue of 2023‒04‒16
two papers selected by
Gabriela Da Silva Xavier
University of Birmingham

Cell Rep. 2023 Apr 10. pii: S2211-1247(23)00387-X. [Epub ahead of print]42(4): 112376

Conformational changes in the negative arm of the circadian clock correlate with dynamic interactomes involved in post-transcriptional regulation.

Jacqueline F Pelham, Alexander E Mosier, Samuel C Altshuler, Morgan L Rhodes, Christopher L Kirchhoff, William B Fall, Catherine Mann, Lisa S Baik, Joanna C Chiu, Jennifer M Hurley.

Biology is tuned to the Earth's diurnal cycle by the circadian clock, a transcriptional/translational negative feedback loop that regulates physiology via transcriptional activation and other post-transcriptional mechanisms. We hypothesize that circadian post-transcriptional regulation might stem from conformational shifts in the intrinsically disordered proteins that comprise the negative arm of the feedback loop to coordinate variation in negative-arm-centered macromolecular complexes. This work demonstrates temporal conformational fluidity in the negative arm that correlates with 24-h variation in physiologically diverse macromolecular complex components in eukaryotic clock proteins. Short linear motifs on the negative-arm proteins that correspond with the interactors localized to disordered regions and known temporal phosphorylation sites suggesting changes in these macromolecular complexes could be due to conformational changes imparted by the temporal phospho-state. Interactors that oscillate in the macromolecular complexes over circadian time correlate with post-transcriptionally regulated proteins, highlighting how time-of-day variation in the negative-arm protein complexes may tune cellular physiology.

Keywords: CP: Genomics; CP: Molecular biology; Drosophila melanogaster; FREQUENCY; Intrinsic Disorder; Neurospora crassa; PERIOD; interactome; negative arm proteins

DOI: https://doi.org/10.1016/j.celrep.2023.112376

Nat Commun. 2023 Apr 08. 14(1): 1994

Circulating blood eNAMPT drives the circadian rhythms in locomotor activity and energy expenditure.

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor of critical enzymes including protein deacetylase sirtuins/SIRTs and its levels in mammalian cells rely on the nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway. Intracellular NAMPT (iNAMPT) is secreted and found in the blood as extracellular NAMPT (eNAMPT). In the liver, the iNAMPT-NAD+ axis oscillates in a circadian manner and regulates the cellular clockwork. Here we show that the hypothalamic NAD+ levels show a distinct circadian fluctuation with a nocturnal rise in lean mice. This rhythm is in phase with that of plasma eNAMPT levels but not with that of hypothalamic iNAMPT levels. Chemical and genetic blockade of eNAMPT profoundly inhibit the nighttime elevations in hypothalamic NAD+ levels as well as those in locomotor activity (LMA) and energy expenditure (EE). Conversely, elevation of plasma eNAMPT by NAMPT administration increases hypothalamic NAD+ levels and stimulates LMA and EE via the hypothalamic NAD+-SIRT-FOXO1-melanocortin pathway. Notably, obese animals display a markedly blunted circadian oscillation in blood eNAMPT-hypothalamic NAD+-FOXO1 axis as well as LMA and EE. Our findings indicate that the eNAMPT regulation of hypothalamic NAD+ biosynthesis underlies circadian physiology and that this system can be significantly disrupted by obesity.

DOI: https://doi.org/10.1038/s41467-023-37517-6