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SLR-2 and JMJC-1 regulate an evolutionarily conserved stress-response network.

ABSTRACT: Maintaining a homeostatic interaction with the environment is crucial for the growth, survival, and propagation of all living organisms. Reestablishment of equilibrium after stress is achieved by the activation of complex transcriptional-response networks, many of which remain poorly understood. Here, we report that the zinc-finger protein, SLR-2, is a master stress regulator and is required for the normal response to pleiotropic stress conditions in Caenorhabditis elegans. Using bioinformatical tools, we identified an evolutionarily conserved nucleotide motif present in slr-2 stress-responsive genes and show that this motif is sufficient for stress induction under a variety of conditions. We also demonstrate that JMJC-1, a conserved Jumonji C domain protein, acts downstream of SLR-2 to mediate stress response in C. elegans. Moreover, the role of JMJC-1 in stress response is conserved in Drosophila and mammals. Finally, we provide evidence that the SLR-2-JMJC-1 pathway functions independently of the well-studied DAF-16/FOXO1 network. These findings point to a previously unrecognized phylogenetically conserved master stress-response pathway in metazoa.

SUBMITTER: Kirienko NV

PROVIDER: S-EPMC2829162 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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SLR-2 and JMJC-1 regulate an evolutionarily conserved stress-response network.

Kirienko Natalia V NV Fay David S DS

The EMBO journal 20100107 4

Maintaining a homeostatic interaction with the environment is crucial for the growth, survival, and propagation of all living organisms. Reestablishment of equilibrium after stress is achieved by the activation of complex transcriptional-response networks, many of which remain poorly understood. Here, we report that the zinc-finger protein, SLR-2, is a master stress regulator and is required for the normal response to pleiotropic stress conditions in Caenorhabditis elegans. Using bioinformatical ...[more]

PMID: 20057358

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Project description:BACKGROUND:Mitochondrial dysfunction causes or contributes to a wide variety of pathologies, including neurodegenerative diseases, cancer, metabolic diseases, and aging. Cells actively surveil a number of mitochondrial readouts to ensure that cellular homeostasis is maintained. RESULTS:In this article, we characterize the role of the ethanol and stress response element (ESRE) pathway in mitochondrial surveillance and show that it is robustly activated when the concentration of reactive oxygen species (ROS) in the cell increases. While experiments were mostly performed in Caenorhabditis elegans, we observed similar gene activation profile in human cell lines. The linear relationship between ROS and ESRE activation differentiates ESRE from known mitochondrial surveillance pathways, such as the mitochondrial unfolded protein response (UPRmt), which monitor mitochondrial protein import. The ability of the ESRE network to be activated by increased ROS allows the cell to respond to oxidative and reductive stresses. The ESRE network works in tandem with other mitochondrial surveillance mechanisms as well, in a fashion that suggests a partially redundant hierarchy. For example, mutation of the UPRmt pathway results in earlier and more robust activation of the ESRE pathway. Interestingly, full expression of ATFS-1, a key transcription factor for the UPRmt, requires the presence of an ESRE motif in its promoter region. CONCLUSION:The ESRE pathway responds to mitochondrial damage by monitoring ROS levels. This response is conserved in humans. The ESRE pathway is activated earlier when other mitochondrial surveillance pathways are unavailable during mitochondrial crises, potentially to mitigate stress and restore health. However, the exact mechanisms of pathway activation and crosstalk remain to be elucidated. Ultimately, a better understanding of this network, and its role in the constellation of mitochondrial and cellular stress networks, will improve healthspan.

Project description:Bovine trypanosomosis is a devastating disease that causes huge economic loss to the global cattle industry on a yearly basis. Selection of accurate biomarkers are important in early disease diagnosis and treatment. Of late, micro-RNAs (miRNAs) are becoming the most useful biomarkers for both infectious and non-infectious diseases in humans, but this is not the case in animals. miRNAs are non-coding RNAs that regulate gene expression through binding to the 3'-, 5'-untranslated regions (UTR) or coding sequence (CDS) region of one or more target genes. The molecular identification of miRNAs that regulates the expression of immune genes responding to bovine trypanosomosis is poorly defined, as is the possibility that these miRNAs could serve as potential biomarkers for disease diagnosis and treatment currently unknown. To this end, we utilized in silico tools to elucidate conserved miRNAs regulating immune response genes during infection, in addition to cataloging significant genes. Based on the p value of 1.77E-32, we selected 25 significantly expressed immune genes. Using prediction analysis, we identified a total of 4,251 bovine miRNAs targeting these selected genes across the 3'UTR, 5'UTR and CDS regions. Thereafter, we identified candidate miRNAs based on the number of gene targets and their abundance at the three regions. In all, we found the top 13 miRNAs that are significantly conserved targeting 7 innate immune response genes, including bta-mir-2460, bta-mir-193a, bta-mir-2316, and bta-mir-2456. Our gene ontology analysis suggests that these miRNAs are involved in gene silencing, cellular protein modification process, RNA-induced silencing complex, regulation of humoral immune response mediated by circulating immunoglobulin and negative regulation of chronic inflammatory response, among others. In conclusion, this study identifies specific miRNAs that may be involved in the regulation of gene expression during bovine trypanosomosis. These miRNAs have the potential to be used as biomarkers in the animal and veterinary research community to facilitate the development of tools for early disease diagnosis/detection, drug targeting, and the rational design of drugs to facilitate disease treatment.

Project description:IntroductionStress may pose a serious challenge to immune homeostasis. Stress however also may prepare the immune system for challenges such as wounding or infection, which are likely to happen during a fight or flight stress response.MethodsIn common carp (Cyprinus carpio L.) we studied the stress-induced redistribution of neutrophils into circulation, and the expression of genes encoding CXC chemokines known to be involved in the regulation of neutrophil retention (CXCL12) and redistribution (CXCL8), and their receptors (CXCR4 and CXCR1-2, respectively) in blood leukocytes and in the fish hematopoietic organ - the head kidney. The potential involvement of CXC receptors and stress hormone receptors in stress-induced neutrophil redistribution was determined by an in vivo study with selective CXCR inhibitors and antagonists of the receptors involved in stress regulation: glucocorticoid/mineralocorticoid receptors (GRs/MRs), adrenergic receptors (ADRs) and the melanocortin 2 receptor (MC2R).ResultsThe stress-induced increase of blood neutrophils was accompanied by a neutrophil decrease in the hematopoietic organs. This increase was cortisol-induced and GR-dependent. Moreover, stress upregulated the expression of genes encoding CXCL12 and CXCL8 chemokines, their receptors, and the receptor for granulocytes colony-stimulation factor (GCSFR) and matrix metalloproteinase 9 (MMP9). Blocking of the CXCR4 and CXCR1 and 2 receptors with selective inhibitors inhibited the stress-induced neutrophil redistribution and affected the expression of genes encoding CXC chemokines and CXCRs as well as GCSFR and MMP9.DiscussionOur data demonstrate that acute stress leads to the mobilization of the immune system, characterized by neutrophilia. CXC chemokines and CXC receptors are involved in this stress-induced redistribution of neutrophils from the hematopoietic tissue into the peripheral blood. This phenomenon is directly regulated by interactions between cortisol and the GR/MR. Considering the pivotal importance of neutrophilic granulocytes in the first line of defense, this knowledge is important for aquaculture, but will also contribute to the mechanisms involved in the stress-induced perturbation in neutrophil redistribution as often observed in clinical practice.

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SLR-2 and JMJC-1 regulate an evolutionarily conserved stress-response network.

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SLR-2 and JMJC-1 regulate an evolutionarily conserved stress-response network.

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