RRC ID 57168
Author Kweon SH, Lee J, Lim C, Choe J.
Title High-Amplitude Circadian Rhythms in Drosophila Driven by Calcineurin-Mediated Post-translational Control of sarah.
Journal Genetics
Abstract Post-translational control is a crucial mechanism for circadian timekeeping. Evolutionarily conserved kinases and phosphatases have been implicated in circadian phosphorylation and the degradation of clock-relevant proteins, which sustain high-amplitude rhythms with 24-hr periodicity in animal behaviors and physiology. Here, we report a novel clock function of the heterodimeric Ca2+/calmodulin-dependent phosphatase calcineurin and its regulator sarah (sra) in Drosophila Genomic deletion of the sra locus dampened circadian locomotor activity rhythms in free-running constant dark after entrainment in light-dark cycles. Poor rhythms in sra mutant behaviors were accompanied by lower expression of two oscillating clock proteins, PERIOD (PER) and TIMELESS (TIM), at the post-transcriptional level. RNA interference-mediated sra depletion in circadian pacemaker neurons was sufficient to phenocopy loss-of-function mutation in sra On the other hand, a constitutively active form of the catalytic calcineurin subunit, Pp2B-14DACT, shortened circadian periodicity in locomotor behaviors and phase-advanced PER and TIM rhythms when overexpressed in clock neurons. Heterozygous sra deletion induced behavioral arrhythmicity in Pp2B-14DACT flies, whereas sra overexpression rescued short periods in these animals. Finally, pharmacological inhibition of calcineurin in either wild-type flies or clock-less S2 cells decreased the levels of PER and TIM, likely by facilitating their proteasomal degradation. Taken together, these data suggest that sra negatively regulates calcineurin by cell-autonomously titrating calcineurin-dependent stabilization of PER and TIM proteins, thereby sustaining high-amplitude behavioral rhythms in Drosophila.
Volume 209(3)
Pages 815-828
Published 2018-7
DOI 10.1534/genetics.118.300808
PII genetics.118.300808
PMID 29724861
PMC PMC6028259
MeSH Animals Calcineurin / metabolism* Calcium-Binding Proteins Cell Line Circadian Rhythm Drosophila / genetics Drosophila / metabolism Drosophila / physiology* Drosophila Proteins / genetics* Drosophila Proteins / metabolism* Gene Deletion Gene Expression Regulation Intracellular Signaling Peptides and Proteins / genetics* Intracellular Signaling Peptides and Proteins / metabolism Period Circadian Proteins / genetics Period Circadian Proteins / metabolism* Protein Processing, Post-Translational Proteolysis
IF 3.564
Times Cited 1