Identification of PCBP1 as a Novel Modulator of Mammalian Circadian Clock

Abstract

The circadian clock governs our daily cycle of behavior and physiology. Previous studies have identified a handful of core clock components and hundreds of circadian modifiers. Here, we report the discovery that poly(C)-binding protein 1 (PCBP1), displaying a circadian expression pattern, was a novel circadian clock regulator. We found that knocking down PCBP1 resulted in period shortening in human U2OS cells, and that manipulations of PCBP1 expression altered the activity of CLOCK/BMAL1 in an E-box-based reporter assay. Further mechanistic study demonstrated that this clock function of PCBP1 appears to work by enhancing the association of Cryptochrome 1 (CRY1) with the CLOCK/BMAL1 complex, thereby negatively regulating the latter’s activation. Co-immunoprecipitation of PCBP1 and core clock molecules confirmed the interactions between PCBP1 and CRY1, and a time-course qPCR assay revealed the rhythmic expression of PCBP1 in mouse hearts in vivo. Given that the RNA interference of mushroom-body expressed (mub), the poly(rC) binding protein (PCBP) homolog of Drosophila, in the clock neurons also led to a circadian phenotype in the locomotor assay, our study deemed PCBP1 a novel clock modifier whose circadian regulatory mechanism is conserved during evolution.

Investigating the neuroprotective potential of rAAV2‐PCBP1‐EGFP gene therapy against a 6‐OHDA‐induced model of Parkinson's disease

“…may also be closely associated with PD, although the exact mechanism remains unclear (Wu et al, 2021). However, to date, no animal experiments have been conducted to investigate the specific mechanism of PCBP1 in regulating the process of PD models.…”

“…Moreover, abnormal nuclear distribution of PCBP1 has been implicated in the pathogenesis of Huntington's disease (HD), suggesting that RBPs, including PCBP1, may play a role in the pathophysiological processes underlying neurodegenerative conditions (Geuens et al., 2017 ). Given the shared pathophysiology between PD and HD, PCBP1 may also be closely associated with PD, although the exact mechanism remains unclear (Wu et al., 2021 ). However, to date, no animal experiments have been conducted to investigate the specific mechanism of PCBP1 in regulating the process of PD models.…”

PCBP-1 Regulates the Transcription and Alternative Splicing of Inflammation and Ubiquitination-Related Genes in PC12 Cell

“…PCBP-1 plays an important role in the regulation of transcription and RNA metabolism at various levels ( Geuens et al, 2017 ). The previous studies have also indicated that PCBP-1 regulates the circadian clock ( Wu et al, 2021 ) as well as maintains the iron homeostasis ( Yanatori et al, 2020 ). Furthermore, abnormal nuclear distribution of PCBP-1 participates in Huntington’s disease (HD) pathogenesis, suggesting that as RBPs, like PCBP-1, may contribute to the pathophysiological processes under neurodegenerative conditions ( Geuens et al, 2017 ; Mori et al, 2019 ).…”