Co-translational quality control of nascent polypeptides times circadian rhythms in Drosophila

Abstract

Ribosome-associated quality control (RQC) is a co-translational surveillance mechanism that senses ribosome collisions as aberrant translation events and triages their intermediates for proteostasis. Nonetheless, how RQC contributes to animal physiology remains elusive. Here, we demonstrate that Drosophila circadian clocks require RQC to sustain 24-hour rhythms in clock gene expression and locomotor behaviors. Genetic losses of the RQC pathway consistently impaired free-running locomotor rhythms in constant dark (DD). Clock neuron-specific depletion of Caliban (Clbn), a Drosophila homolog of the evolutionarily conserved RQC factor that mediates nascent polypeptide degradation via the C-terminal alanine and threonine (CAT) tailing, was sufficient to cause long periods in DD behaviors. Overexpression of a Clbn mutant allele defective for CAT-tailing also phenocopied CLBN depletion. The Clbn deficiency delayed rhythmic expression of the circadian clock protein PERIOD (PER), but not TIMELESS (TIM). Clbn genetically interacted with twenty-four and Ataxin-2, two key components of the PER translation activator complex, on the periodicity of DD behaviors. Nonetheless, CLBN associated with TIM and CLBN-depletion behaviors were masked by TIM overexpression. Given the critical role of the PER-TIM complex in circadian timing, we propose that daily reconstitution of the PER-TIM complex is intimately coupled to their co-translational surveillance for fine-tuning molecular clocks and behavioral rhythms on a 24-hour timescale.