Rege Movie Download

[Nayra Waddles]

KaushalRege is Fulton Faculty Impact Profesor at ASU and is member of the graduate faculty of Chemical Engineering, Biomedical Engineering, Biological Design, Materials Science and Engineering, and School of Molecular Sciences. He completed his doctorate in Chemical Engineering at Rensselaer Polytechnic Institute and went on to postdoctoral research with Massachusetts General Hospital and Harvard Medical School in Boston, MA.

Research in the Rege Bioengineering laboratory in at the forefront of develping biomaterial and nanomateirals for tissue repair and therapeutic delivery. Rege has made notable progress with photothermal nanomaterials, using them with polymers and polypeptides to repair body tissues. His research findings have major implications for repair and regeneration of ruptured intestines, colorectal tissue and the repair of skin injuries.

His work has attracted funding from the the National Institutes of Health, National Science Foundation, and the Mayo Clinic Center for Regenerative Medicine. In recent years, his research findings have been featured in several leading science and engineering news publications, including Scientific American. He waseected as Fellow of the American Institute of Medical and Biological Engineers (AIMBE) in 2017, received the New Investigator Award from the American Society of Photobiology in 2014 and a Young Investigator Award from the Defense Threat Reduction Agency (DoD) for developing smart materials for sensor technology used in military intelligence and defense systems.

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Metabolic pathways are known to sense the environmental stimuli and result in physiological adjustments. The responding processes need to be tightly controlled. Here, we show that upon encountering P. aeruginosa, C. elegans upregulate the transcription factor ets-4, but this upregulation is attenuated by the ribonuclease, rege-1. As such, mutants with defective REGE-1 ribonuclease activity undergo ets-4-dependent early death upon challenge with P. aeruginosa. Furthermore, mRNA-seq analysis revealed associated global changes in two key metabolic pathways, the IIS (insulin/IGF signaling) and TOR (target of rapamycin) kinase signaling pathways. In particular, failure to degrade ets-4 mRNA in activity-defective rege-1 mutants resulted in upregulation of class II longevity genes, which are suppressed during longevity, and activation of TORC1 kinase signaling pathway. Genetic inhibition of either pathway way was sufficient to abolish the poor survival phenotype in rege-1 worms. Further analysis of ETS-4 ChIP data from ENCODE and characterization of one upregulated class II gene, ins-7, support that the Class II genes are activated by ETS-4. Interestingly, deleting an upregulated Class II gene, acox-1.5, a peroxisome β-oxidation enzyme, largely rescues the fat lost phenotype and survival difference between rege-1 mutants and wild-types. Thus, rege-1 appears to be crucial for animal survival due to its tight regulation of physiological responses to environmental stimuli. This function is reminiscent of its mammalian ortholog, Regnase-1, which modulates the intestinal mTORC1 signaling pathway.

Eukaryotes rely on tightly regulated insulin-IGF signaling and TOR pathways to maintain proper cellular processes such as metabolism, aging, and pathogen defense, which allow them to sense and respond to changes in nutrient availability and environmental stress. While Regnase-1 is known for its role in regulating immune response in mammals, the importance of its ortholog, rege-1, in C. elegans was previously unclear. Our study revealed that rege-1 participates in regulating the TOR signaling pathway, which subsequently affects C. elegans lifespan and pathogen defense. By post-transcriptionally regulating the ets-4 transcription factor, rege-1 is able to regulate a set of longevity-suppressed genes, including those involved in the peroxisome fatty acid β-oxidation pathway, likely affecting the level of acetyl-COA and modulating the TOR signaling pathway. Our findings indicate that defective rege-1 leads to an excess of ets-4, which activates the lipid β-oxidation pathway and further activates the TOR pathway, ultimately reducing lifespan and survival through pathogen and fat loss.

Copyright: 2023 Tsai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

The TOR kinase pathway is crucial for regulating cell growth by interpreting signals related to nutrient availability [7]. The main complex involved in this process is TOR complex 1 (TORC1), which is activated by both phosphorylation and acetylation upon detection of nutrients. Akt, a protein kinase, is responsible for phosphorylating TOR kinase, while EP300, an acetyltransferase, acetylates Raptor, a key adaptor protein in the TORC1 [8]. The activation of TORC1 kinase activity also requires the GTP-bound RHEB, and the heterodimeric Rag GTPase (composed of RAGA and RAGC) is essential for recruiting activated TORC1 to lysosomes to continue the TORC1 signaling cascade [7]. This cascade enhances the phosphorylation of S6 ribosomal proteins and 4EBP1, further promoting translation. Additionally, the activation of TORC1 signaling inhibits the activation of autophagy by preventing the formation of the ULK complex, the initiation complex [9]

The level of acetyl-CoA plays a crucial role in the acetylation of Raptor [10]. In amino acid-starved cells, TORC1 signaling is activated by supplementing with acetyl-CoA. Acetyl-CoA can be derived from various nutrients such as pyruvate, amino acids, and fatty acid β-oxidation [8]. However, a study on modulating fatty liver formation in fasting or high fat diet mice has shown that blocking the liver peroxisome fatty acid β-oxidation pathway by deleting acyl-CoA Oxidase 1 (ACOX1) is sufficient to reduce fatty liver due to decreases in acetyl-CoA, which consequently results in decreased TORC1 signaling and activates autophagy [8,10].

Regnase-1 contains a ZC3h12A-like ribonuclease domain and a CCCH zinc finger domain and is only present in multicellular eukaryotes, with no homologs found in bacteria or fungi [18]. In C. elegans, the only Regnase-1 protein ortholog is REGE-1, which specifically targets ets-4 mRNA, an ets (E-twenty-six-specific sequence) transcription factor [19,20]. It is worth noting that while ets genes are widely distributed among metazoans, no ets genes have been identified in protozoans [21]. Previous research has demonstrated that rege-1 mutants exhibit a significant loss of fat, and mRNAseq analysis has revealed the upregulation of lipid catabolic and immune-related genes [22]. Interestingly, genetic studies have shown that the combination of an ets-4 mutation and a rege-1 mutation is sufficient to restore normal fat levels and prevent immune gene misregulation. However, how these two newly evolved metazoan proteins participate in C. elegans cellular processes and survival remains largely unknown. Specifically, whether an excess of ETS-4 results in detrimental effects in C. elegans and needs to be regulated by REGE-1 is still yet to be determined.

ETS-4 contains both an ETS DNA binding domain and a PNT domain. Previous studies have shown that deleting ets-4 leads to a longer lifespan and increased cold tolerance [23,24]. However, ETS-4 is not always associated with negative effects in C. elegans, as it has been found to be essential for axon regeneration by promoting the expression of a receptor tyrosine kinase, SVH-2 [25]. While ETS proteins are capable of acting as either transcriptional activators or repressors, ets-4 has been shown to primarily function as a transcriptional activator, as evidenced by studies in yeast and mouse fibroblast reporter systems [24]. Additionally, the localization of ETS-4 appears to be dynamic. While ETS-4 is observed in the nucleus of neuron, pharyngeal and embryonic intestinal cells, it is less frequent in the nucleus of adult intestinal cells [24]. However, the nuclear localization of ETS-4 is increased in adult intestinal cells during cold stress or in the presence of a rege-1 mutant background [22,23].

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