RAE1 promotes BMAL1 shuttling and regulates degradation and activity of CLOCK: BMAL1 heterodimer

Abstract

Circadian rhythm is an autoregulatory rhythm, which is sustained by various mechanisms. The nucleocytoplasmic shuttling of BMAL1 is essential for CLOCK translocation between cytoplasm and nucleus and maintenance of the correct pace of the circadian clock. Here we showed that RAE1 and NUP98 can promote the degradation of BMAL1 and CLOCK. Knockdown of RAE1 and NUP98 suppressed BMAL1 shuttling, leading to cytoplasm accumulation of CLOCK. Furthermore, Chip assay showed that knockdown of RAE1 and NUP98 can enhance the interaction between CLOCK: BMAL1 and E-box region in the promoters of Per2 and Cry1 while reducing its transcription activation activity. Our present study firstly revealed that RAE1 and NUP98 are critical regulators for BMAL1 shuttling.

Overexpression of SARS-CoV-2 protein ORF6 dislocates RAE1 and NUP98 from the nuclear pore complex

“…We and others showed that RAE1 binds to the GLEBS motif of NUP98, allowing them to interact and function together in mRNA export or spindle assembly to prevent chromosome mis-segregation [ [10] , [11] , [12] , [13] , [14] , [15] ]. RAE1 and NUP98, which are kinetically partitioned among other components in both cytoplasmic and nuclear compartments, also act as regulators for BMAL1 shuttling between the cytoplasm and nucleus, as well as maintenance of the correct pace of the circadian clock [ 16 ]. In addition, RAE1 was found to mediate ZEB1 expression by promoting epithelial-mesenchymal transition in breast cancer [ 17 ].…”

The Participation of the Intrinsically Disordered Regions of the bHLH-PAS Transcription Factors in Disease Development

“…Formation of nuclear bodies containing BMAL1/CBP provides transcriptionally active sites of target genes [89] and support our thesis about putative role of BMAL1 in LLPS formation. Similarly to other bHLH-PAS TFs Bmal 1 is shuttling protein [90] and phosphorylation regulates localization signal activity [91]. Interestingly, BMAL1 was shown to stimulate also translation by interactions with the translational machinery in the cytosol after S42 phosphorylation [92].…”

Post-Translational Mechanisms of Plant Circadian Regulation

“…Since the coordinated action of core clock proteins helps orchestrate the transcription of output genes in the nucleus, the nuclear translocation of these proteins is a pivotal regulatory point. The control of nuclear entry of key clock proteins in metazoans is often through phosphorylation or dimerization [118,119], and can also involve interaction with nuclear pore-related components and large cytosolic complexes (e.g NRON) [120][121][122][123]. While nucleocytoplasmic trafficking has been well-studied in plants [124,125], little is known of its role in the circadian system.…”