The circadian clock synchronizes biological processes to daily cycles of light and temperature. Clock components, including CIRCADIAN CLOCK-ASSOCIATED1 (CCA1), are also associated with cold acclimation. However, it is unknown how CCA1 activity is modulated in coordinating circadian rhythms and cold acclimation. Here, we report that self-regulation of Arabidopsis thaliana CCA1 activity by a splice variant, CCA1b, links the clock to cold acclimation. CCA1b interferes with the formation of CCA1a-CCA1a and LATE ELONGATED HYPOCOTYL (LHY)-LHY homodimers, as well as CCA1a-LHY heterodimers, by forming nonfunctional heterodimers with reduced DNA binding affinity. Accordingly, the periods of circadian rhythms were shortened in CCA1b-overexpressing transgenic plants (35S:CCA1b), as observed in the cca1 lhy double mutant. In addition, the elongated hypocotyl and leaf petiole phenotypes of CCA1a-overexpressing transgenic plants (35S:CCA1a) were repressed by CCA1b coexpression. Notably, low temperatures suppressed CCA1 alternative splicing and thus reduced CCA1b production. Consequently, whereas the 35S:CCA1a transgenic plants exhibited enhanced freezing tolerance, the 35S:CCA1b transgenic plants were sensitive to freezing, indicating that cold regulation of CCA1 alternative splicing contributes to freezing tolerance. On the basis of these findings, we propose that dynamic self-regulation of CCA1 underlies the clock regulation of temperature responses in Arabidopsis.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor's glucoselowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1β secretion compared to sulfonylurea accompanied by increased serum β-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects.
AMP-activated protein kinase (AMPK) functions as an energy sensor to provide metabolic adaptations under the ATP-deprived conditions such as hypoxia. In the present study, we considered a role of AMPK in the adaptive response to hypoxia by examining whether AMPK is involved in the regulation of hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor that is critical for hypoxic induction of physiologically important genes. We demonstrate that hypoxia or CoCl 2 rapidly activated AMPK in DU145 human prostate cancer cells, and its activation preceded the induction of HIF-1␣ expression. Under these conditions, blockade of AMPK activity by a pharmacological or molecular approach significantly attenuated hypoxia-induced responses such as HIF-1 target gene expression, secretion of vascular endothelial growth factor, glucose uptake, and HIF-1-dependent reporter gene expression, indicating that AMPK is critical for the HIF-1 transcriptional activity and its target gene expression. Its functional requirement for HIF-1 activity was also demonstrated in several different cancer cell lines, but AMPK activation alone was not sufficient to stimulate the HIF-1 transcriptional activity. We further present data showing that AMPK transmits a positive signal for HIF-1 activity via a signaling pathway that is independent of phosphatidylinositol 3-kinase/AKT and several mitogen-activated protein kinases. Taken together, our results suggest that AMPK is a novel and critical component of HIF-1 regulation, implying its new roles in oxygen-regulated cellular phenomena.The energy status of the cell plays a crucial role for cell survival, and exposure of eukaryotic cells to metabolic stresses that accompany the depletion of intracellular ATP triggers specific and systemic adaptive responses. AMP-activated protein kinase (AMPK), 1 a heterotrimeric enzyme consisting of a catalytic subunit (␣) and two regulatory subunits ( and ␥), plays a critical role as an energy sensor in these responses (reviewed in Refs. 1-3). In response to nutritional or environmental stress factors that deplete intracellular ATP, AMPK is activated by allosteric binding of AMP (4, 5) and by phosphorylation by a still uncharacterized upstream AMPK kinase (6). Once activated, AMPK minimizes further ATP consumption by suppressing ATP-consuming anabolic pathways as well as activating ATP-generating catabolic pathways. The physiological or stress conditions known to activate AMPK include exercise (7-9), nutritional starvation (10), heat shock (11), oxidative stress (12), and ischemia/hypoxia (3, 13-15). Similar to the intracellular energy status, cellular oxygen concentration is precisely regulated in mammals to maintain cellular function and integrity. The reduced oxygen availability also initiates a series of adaptive responses, and many of these are mediated by HIF-1, which trans-activates several dozens of target genes whose protein products function to increase oxygen delivery and to enhance metabolic adaptation to anaerobic conditions (reviewed in Re...
During cold acclimation, C-repeat binding factors (CBFs) activate downstream targets, such as cold-regulated genes, leading to the acquisition of freezing tolerance in plants. Inducer of CBF expression 1 (ICE1) plays a key role by activating CBF3 expression in shaping the cold-induced transcriptome. While the ICE1-CBF3 regulon constitutes a major cold acclimation pathway, gene regulatory networks governing the CBF signaling are poorly understood. Here, we demonstrated that ICE1 and its paralog ICE2 induce CBF1, CBF2, and CBF3 by binding to the gene promoters. ICE2, like ICE1, was ubiquitinated by the high expression of osmotically responsive gene 1 (HOS1) E3 ubiquitin ligase. Whereas ICE2-defective ice2-2 mutant did not exhibit any discernible freezing-sensitive phenotypes, ice1-2 ice2-2/+ plant, which is defective in ICE1 and has a heterozygotic ice2 mutation, exhibited significantly reduced freezing tolerance. Accordingly, all three CBF genes were markedly down-regulated in the ice1-2 ice2-2/+ plant, indicating that ICE1 and ICE2 are functionally redundant with different implementations in inducing CBF genes. Together with the negative regulation of CBF3 by CBF2, we propose that the unified ICE-CBF pathway provides a transcriptional feedback of freezing tolerance to sustain plant development and survival during cold acclimation.
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