Hsp70s regulate circadian rhythm by interacting with PERIOD

Circadian rhythms synchronize life with the environment. Although the molecular feedback loop underlying these rhythms has been well-characterized, our understanding of cellular clocks remains incomplete. In this study, by applying cellular and biochemistry approaches, we reveal the involvement of Hsp70 family proteins in regulating the core clock feedback loop by modulating the condensation formation of the PERIOD (PER) protein. Mutations in Hsp70s lead to circadian rhythm defects in a temperature-dependent manner. Further mechanistic investigation uncovered that Hsp70s compete with TIM for binding to PER. Notably, Hsp70s are essential for reducing PER liquid condensates. By generating a complete null allele of per, we demonstrated that per functions downstream of Hsp70s. Our findings on the role of Hsp70s in regulating PER provide new insights into the cellular mechanisms governing circadian rhythms.