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Comparing the yeast retrograde response and NF-?B stress responses: implications for aging.

ABSTRACT: The mitochondrial retrograde response has been extensively described in Saccharomyces cerevisiae, where it has been found to extend life span during times of mitochondrial dysfunction, damage or low nutrient levels. In yeast, the retrograde response genes (RTG) convey these stress responses to the nucleus to change the gene expression adaptively. Similarly, most classes of higher organisms have been shown to have some version of a central stress-mediating transcription factor, NF-?B. There have been several modifications along the phylogenetic tree as NF-?B has taken a larger role in managing cellular stresses. Here, we review similarities and differences in mechanisms and pathways between RTG genes in yeast and NF-?B as seen in more complex organisms. We perform a structural homology search and reveal similarities of Rtg proteins with eukaryotic transcription factors involved in development and metabolism. NF-?B shows more sophisticated functions when compared to RTG genes including participation in immune responses and induction of apoptosis under high levels of ROS-induced mitochondrial and nuclear DNA damage. Involvement of NF-?B in chromosomal stability, coregulation of mitochondrial respiration, and cross talk with the TOR (target of rapamycin) pathway points to a conserved mechanism also found in yeast.

SUBMITTER: Srinivasan V

PROVIDER: S-EPMC2980572 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Comparing the yeast retrograde response and NF-κB stress responses: implications for aging.

Srinivasan Visish V Kriete Andres A Sacan Ahmet A Jazwinski S Michal SM

Aging cell 20101021 6

The mitochondrial retrograde response has been extensively described in Saccharomyces cerevisiae, where it has been found to extend life span during times of mitochondrial dysfunction, damage or low nutrient levels. In yeast, the retrograde response genes (RTG) convey these stress responses to the nucleus to change the gene expression adaptively. Similarly, most classes of higher organisms have been shown to have some version of a central stress-mediating transcription factor, NF-κB. There have ...[more]

PMID: 20961379

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Project description:BackgroundIncreasing evidence indicates that neuroinflammation is a critical factor contributing to the progression of various neurodegenerative diseases. The IKK/NF-κB signalling system is a central regulator of inflammation, but it also affects neuronal survival and differentiation. A complex interplay between different CNS resident cells and infiltrating immune cells, which produce and respond to various inflammatory mediators, determines whether neuroinflammation is beneficial or detrimental. The IKK/NF-κB system is involved in both production of and responses to these mediators, although the precise contribution depends on the cell type as well as the cellular context, and is only partially understood. Here we investigated the specific contribution of neuronal IKK/NF-κB signalling on the regulation of neuroinflammatory processes and its consequences. To address this issue, we established and analysed a conditional gain-of-function mouse model that expresses a constitutively active allele of IKK2 in principal forebrain neurons (IKK2nCA). Proinflammatory gene and growth factor expression, histopathology, microgliosis, astrogliosis, immune cell infiltration and spatial learning were assessed at different timepoints after persistent canonical IKK2/NF-κB activation.ResultsIn contrast to other cell types and organ systems, chronic IKK2/NF-κB signalling in forebrain neurons of adult IKK2nCA animals did not cause a full-blown inflammatory response including infiltration of immune cells. Instead, we found a selective inflammatory response in the dentate gyrus characterized by astrogliosis, microgliosis and Tnf-α upregulation. Furthermore, downregulation of the neurotrophic factor Bdnf correlated with a selective and progressive atrophy of the dentate gyrus and a decline in hippocampus-dependent spatial learning. Neuronal degeneration was associated with increased Fluoro-jade staining, but lacked activation of apoptosis. Remarkably, neuronal loss could be partially reversed when chronic IKK2/NF-κB signalling was turned off and Bdnf expression was restored.ConclusionOur results demonstrate that persistent IKK2/NF-κB signalling in forebrain neurons does not induce overall neuroinflammation, but elicits a selective inflammatory response in the dentate gyrus accompanied by decreased neuronal survival and impaired learning and memory. Our findings further suggest that chronic activation of neuronal IKK2/NF-κB signalling, possibly as a consequence of neuroinflammatory conditions, is able to induce apoptosis-independent neurodegeneration via paracrine suppression of Bdnf synthesis.

Project description:Tumor necrosis factor (TNF) is a pleiotropic cytokine whose primary physiological function involves coordinating inflammatory and adaptive immune responses. However, uncontrolled TNF signaling causes aberrant inflammation and has been implicated in several human ailments. Therefore, an understanding of the molecular mechanisms underlying dynamical and gene controls of TNF signaling bear significance for human health. As such, TNF engages the canonical nuclear factor kappa B (NF-κB) pathway to activate RelA:p50 heterodimers, which induce expression of specific immune response genes. Brief and chronic TNF stimulation produces transient and long-lasting NF-κB activities, respectively. Negative feedback regulators of the canonical pathway, including IκBα, are thought to ensure transient RelA:p50 responses to short-lived TNF signals. The non-canonical NF-κB pathway mediates RelB activity during immune differentiation involving p100. We uncovered an unexpected role of p100 in TNF signaling. Brief TNF stimulation of p100-deficient cells triggered an additional late NF-κB activity consisting of RelB:p50 heterodimers, which modified the TNF-induced gene-expression program. In p100-deficient cells subjected to brief TNF stimulation, RelB:p50 not only sustained the expression of a subset of RelA-target immune response genes but also activated additional genes that were not normally induced by TNF in WT mouse embryonic fibroblasts (MEFs) and were related to immune differentiation and metabolic processes. Despite this RelB-mediated distinct gene control, however, RelA and RelB bound to mostly overlapping chromatin sites in p100-deficient cells. Repeated TNF pulses strengthened this RelB:p50 activity, which was supported by NF-κB-driven RelB synthesis. Finally, brief TNF stimulation elicited late-acting expressions of NF-κB target pro-survival genes in p100-deficient myeloma cells. In sum, our study suggests that the immune-differentiation regulator p100 enforces specificity of TNF signaling and that varied p100 levels may provide for modifying TNF responses in diverse physiological and pathological settings.

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Comparing the yeast retrograde response and NF-?B stress responses: implications for aging.

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Comparing the yeast retrograde response and NF-κB stress responses: implications for aging.

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