High-Amplitude Circadian Rhythms in Drosophila Driven by Calcineurin-Mediated Post-translational Control of sarah

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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-14D(ACT), 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-14D(ACT) 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.
Publisher
GENETICS SOCIETY AMERICA
Issue Date
2018-07
Language
English
Article Type
Article
Keywords

SYNDROME CRITICAL REGION; CLOCKWORK-ORANGE; TRANSCRIPTIONAL REPRESSOR; PACEMAKER NEURONS; GENE-EXPRESSION; PERIOD PROTEIN; DOWN-SYNDROME; POSTTRANSCRIPTIONAL REGULATION; STRIATED-MUSCLES; BINDING PROTEIN

Citation

GENETICS, v.209, no.3, pp.815 - 828

ISSN
0016-6731
DOI
10.1534/genetics.118.300808
URI
http://hdl.handle.net/10203/244664
Appears in Collection
BS-Journal Papers(저널논문)
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