Protein phosphatase 4 controls circadian clock dynamics by modulating CLOCK/BMAL1 activity

Jul 24, 2021Genes & development

Protein phosphatase 4 may regulate daily body clock by changing CLOCK/BMAL1 activity

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Abstract

Genetic depletion of protein phosphatase 4 (PPP4) shortens the circadian period in human cells.

Circadian rhythms are regulated by post-translational modifications of clock proteins, with phosphorylation being a key factor.
Protein phosphatase 4 (PPP4) and its regulatory subunit PPP4R2 are identified as critical components of the circadian system.
Overexpression of PPP4 lengthens the circadian period, while its depletion has the opposite effect.
PPP4 inhibits the activity of the CLOCK/BMAL1 complex by binding to BMAL1 and counteracting its phosphorylation.
This interaction increases CLOCK/BMAL1 DNA occupancy and decreases its transcriptional activity, affecting circadian timing.

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In all organisms with circadian clocks, post-translational modifications of clock proteins control the dynamics of circadian rhythms, with phosphorylation playing a dominant role. All major clock proteins are highly phosphorylated, and many kinases have been described to be responsible. In contrast, it is largely unclear whether and to what extent their counterparts, the phosphatases, play an equally crucial role. To investigate this, we performed a systematic RNAi screen in human cells and identified protein phosphatase 4 (PPP4) with its regulatory subunit PPP4R2 as critical components of the circadian system in both mammals andGenetic depletion of PPP4 shortens the circadian period, whereas overexpression lengthens it. PPP4 inhibits CLOCK/BMAL1 transactivation activity by binding to BMAL1 and counteracting its phosphorylation. This leads to increased CLOCK/BMAL1 DNA occupancy and decreased transcriptional activity, which counteracts the "kamikaze" properties of CLOCK/BMAL1. Through this mechanism, PPP4 contributes to the critical delay of negative feedback by retarding PER/CRY/CK1δ-mediated inhibition of CLOCK/BMAL1. Drosophila

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Protein phosphatase 4 controls circadian clock dynamics by modulating CLOCK/BMAL1 activity

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