Stress-Induced Low Complexity RNA Activates Physiological Amyloidogenesis.
Ontology highlight
ABSTRACT:
SUBMITTER: Wang M
PROVIDER: S-EPMC6249693 | biostudies-literature | 2018 Aug
REPOSITORIES: biostudies-literature
Publications
Stress-Induced Low Complexity RNA Activates Physiological Amyloidogenesis.
Wang Miling M Tao Xianzun X Jacob Mathieu D MD Bennett Clayton A CA Ho J J David JJD Gonzalgo Mark L ML Audas Timothy E TE Lee Stephen S
Cell reports 20180801 7
Amyloid bodies (A-bodies) are inducible membrane-less nuclear compartments composed of heterogeneous proteins that adopt an amyloid-like state. A-bodies are seeded by noncoding RNA derived from stimuli-specific loci of the rDNA intergenic spacer (rIGSRNA). This raises the question of how rIGSRNA recruits a large population of diverse proteins to confer A-body identity. Here, we show that long low-complexity dinucleotide repeats operate as the architectural determinants of rIGSRNA. On stimulus, c ...[more]
Similar Datasets
Project description:Cholesterol dyshomeostasis has been linked to the pathogenesis of sporadic Alzheimer's disease (AD). In furthering the understanding of mechanisms by which increased levels of circulating cholesterol augments the risk of developing sporadic AD, others and we have reported that low-density lipoprotein (LDL) enters brain parenchyma by disrupting the blood-brain barrier and that endolysosome de-acidification plays a role in LDL-induced amyloidogenesis in neurons. Here, we tested the hypothesis that endolysosome de-acidification was central to amyloid-β (Aβ) generation and that acidifying endolysosomes protects against LDL-induced increases in Aβ levels in neurons. We demonstrated that LDL, but not HDL, de-acidified endolysosomes and increased intraneuronal and secreted levels of Aβ. ML-SA1, an agonist of endolysosome-resident TRPML1 channels, acidified endolysosomes, and TRPML1 knockdown attenuated ML-SA1-induced endolysosome acidification. ML-SA1 blocked LDL-induced increases in intraneuronal and secreted levels of Aβ as well as Aβ accumulation in endolysosomes, prevented BACE1 accumulation in endolysosomes, and decreased BACE1 activity levels. LDL downregulated TRPML1 protein levels, and TRPML1 knockdown worsens LDL-induced increases in Aβ. Our findings suggest that endolysosome acidification by activating TRPML1 may represent a protective strategy against sporadic AD.
| S-EPMC6425476 | biostudies-literature
Project description:More than 98% of the mammalian genome is noncoding, and interspersed transposable elements account for ?50% of noncoding space. Here, we demonstrate that a specific interaction between the polycomb protein EZH2 and RNA made from B2 SINE retrotransposons controls stress-responsive genes in mouse cells. In the heat-shock model, B2 RNA binds stress genes and suppresses their transcription. Upon stress, EZH2 is recruited and triggers cleavage of B2 RNA. B2 degradation in turn upregulates stress genes. Evidence indicates that B2 RNA operates as a "speed bump" against advancement of RNA polymerase II, and temperature stress releases the brakes on transcriptional elongation. These data attribute a new function to EZH2 that is independent of its histone methyltransferase activity and reconcile how EZH2 can be associated with both gene repression and activation. Our study reveals that EZH2 and B2 together control activation of a large network of genes involved in thermal stress.
| S-EPMC5552366 | biostudies-literature
Project description:In Candida glabrata, the transcription factor CgRds2 has been previously characterized as a regulator of glycerophospholipid metabolism, playing a crucial role in the response to osmotic stress. Here, we report that CgRds2 is also involved in the response to pH 2.0 stress. At pH 2.0, the deletion of CgRDS2 led to reduced cell growth and survival, by 33% and 57%, respectively, compared with those of the wild-type strain. These adverse phenotypes resulted from the downregulation of genes related to energy metabolism in the Cgrds2Δ strain at pH 2.0, which led to a 34% reduction of the intracellular ATP content and a 24% decrease in membrane permeability. In contrast, the overexpression of CgRDS2 rescued the growth defect of the Cgrds2Δ strain and increased cell survival at pH 2.0 by 17% compared with that of the wild-type strain, and this effect was accompanied by significant increases in ATP content and membrane permeability, by 42% and 19%, respectively. Furthermore, we found that the calcium/calmodulin-dependent protein kinase (CaMK) CgCmk1 physically interacts with the PAS domain of CgRds2, and CgCmk1 is required for CgRds2 activation and translocation from the cytoplasm to the nucleus under pH 2.0 stress. Moreover, CgCmk1 is critical for CgRds2 function in resistance to pH 2.0 stress, because cells of the Cgrds2-pas strain with a disrupted CgCmk1-CgRds2 interaction exhibited impaired energy metabolism and membrane permeability at pH 2.0. Therefore, our results indicate that CgCmk1 positively regulates CgRds2 and suggest that they promote resistance to low-pH stress by enhancing energy metabolism and membrane permeability in C. glabrataIMPORTANCE An acidic environment is the main problem in the production of organic acids in C. glabrata The present study reports that the calcium/calmodulin-dependent protein kinase CgCmk1 positively regulates CgRds2 to increase intracellular ATP content, membrane permeability, and resistance to low-pH stress. Hence, the transcription factor CgRds2 may be a potential target for improving the acid stress tolerance of C. glabrata during the fermentation of organic acids. The present study also establishes a new link between the calcium signaling pathway and energy metabolism.
| S-EPMC7237787 | biostudies-literature
Project description:There are multiple definitions for low complexity regions (LCRs) in protein sequences, with all of them broadly considering LCRs as regions with fewer amino acid types compared to an average composition. Following this view, LCRs can also be defined as regions showing composition bias. In this critical review, we focus on the definition of sequence complexity of LCRs and their connection with structure. We present statistics and methodological approaches that measure low complexity (LC) and related sequence properties. Composition bias is often associated with LC and disorder, but repeats, while compositionally biased, might also induce ordered structures. We illustrate this dichotomy, and more generally the overlaps between different properties related to LCRs, using examples. We argue that statistical measures alone cannot capture all structural aspects of LCRs and recommend the combined usage of a variety of predictive tools and measurements. While the methodologies available to study LCRs are already very advanced, we foresee that a more comprehensive annotation of sequences in the databases will enable the improvement of predictions and a better understanding of the evolution and the connection between structure and function of LCRs. This will require the use of standards for the generation and exchange of data describing all aspects of LCRs.Short abstractThere are multiple definitions for low complexity regions (LCRs) in protein sequences. In this critical review, we focus on the definition of sequence complexity of LCRs and their connection with structure. We present statistics and methodological approaches that measure low complexity (LC) and related sequence properties. Composition bias is often associated with LC and disorder, but repeats, while compositionally biased, might also induce ordered structures. We illustrate this dichotomy, plus overlaps between different properties related to LCRs, using examples.
| S-EPMC7299295 | biostudies-literature
Project description:Many weakly basic, lipophilic drugs accumulate in lysosomes and exert complex, pleiotropic effects on organelle structure and function. Thus, modeling how perturbations of lysosomal physiology affect the maintenance of lysosomal ion homeostasis is necessary to elucidate the key factors which determine the toxicological effects of lysosomotropic agents, in a cell-type dependent manner. Accordingly, a physiologically-based mathematical modeling and simulation approach was used to explore the dynamic, multi-parameter phenomenon of lysosomal stress. With this approach, parameters that are either directly involved in lysosomal ion transportation or lysosomal morphology were transiently altered to investigate their downstream effects on lysosomal physiology reflected by the changes they induce in lysosomal pH, chloride, and membrane potential. In addition, combinations of parameters were simultaneously altered to assess which parameter was most critical for recovery of normal lysosomal physiology. Lastly, to explore the relationship between organelle morphology and induced stress, we investigated the effects of parameters controlling organelle geometry on the restoration of normal lysosomal physiology following a transient perturbation. Collectively, our results indicate a key, interdependent role of V-ATPase number and membrane proton permeability in lysosomal stress tolerance. This suggests that the cell-type dependent regulation of V-ATPase subunit expression and turnover, together with the proton permeability properties of the lysosomal membrane, is critical to understand the differential sensitivity or resistance of different cell types to the toxic effects of lysosomotropic drugs.
| S-EPMC5678708 | biostudies-literature
Project description:The isotopic niche has become an established concept in trophic ecology. However, the assumptions behind this approach have rarely been evaluated. Evidence is accumulating that physiological stress can affect both magnitude and inter-individual variability of the isotopic signature in consumers via alterations in metabolic pathways. We hypothesized that stress factors (inadequate nutrition, parasite infestations, and exposure to toxic substances or varying oxygen conditions) might lead to suboptimal physiological performance and altered stable isotope signatures. The latter can be misinterpreted as alterations in isotopic niche. This hypothesis was tested by inducing physiological stress in the deposit-feeding amphipod Monoporeia affinis exposed to either different feeding regimes or contaminated sediments. In the amphipods, we measured body condition indices or reproductive output to assess growth status and δ13C and δ15N values to derive isotope niche metrics. As hypothesized, greater isotopic niche estimates were derived for the stressed animals compared to the control groups. Moreover, the δ15N values were influenced by body size, reproductive status and parasite infestations, while δ13C values were influenced by body size, oxygen conditions and survival. Using regression analysis with isotope composition and growth variables as predictors, we were able to discriminate between the amphipods exposed to nutritionally or chemically stressful conditions and those in the control groups. Thus, interpretation of isotopic niche can be confounded by natural or anthropogenic stressors that may induce an apparent change in isotopic niche. These findings stress the importance of including measures of growth and health status when evaluating stable isotope data in food web studies.
| S-EPMC5830748 | biostudies-literature
Project description:YAP is the major downstream effector of the Hippo pathway, which controls cell growth, tissue homeostasis, and organ size. Aberrant YAP activation, resulting from dysregulation of the Hippo pathway, is frequently observed in human cancers. YAP is a transcription co-activator, and the key mechanism of YAP regulation is its nuclear and cytoplasmic translocation. The Hippo pathway component, LATS, inhibits YAP by phosphorylating YAP at Ser127, leading to 14-3-3 binding and cytoplasmic retention of YAP Here, we report that osmotic stress stimulates transient YAP nuclear localization and increases YAP activity even when YAP Ser127 is phosphorylated. Osmotic stress acts via the NLK kinase to induce YAP Ser128 phosphorylation. Phosphorylation of YAP at Ser128 interferes with its ability to bind to 14-3-3, resulting in YAP nuclear accumulation and induction of downstream target gene expression. This osmotic stress-induced YAP activation enhances cellular stress adaptation. Our findings reveal a critical role for NLK-mediated Ser128 phosphorylation in YAP regulation and a crosstalk between osmotic stress and the Hippo pathway.
| S-EPMC5210094 | biostudies-literature
Project description:The tumor-suppressor protein p53 is tightly controlled in normal cells by its two negative regulators--the E3 ubiquitin ligase MDM2 and its homolog MDMX. Under stressed conditions such as DNA damage, p53 escapes MDM2- and MDMX-mediated functional inhibition and degradation, acting to prevent damaged cells from proliferating through induction of cell cycle arrest, DNA repair, senescence or apoptosis. Ample evidence suggests that stress signals induce phosphorylation of MDM2 and MDMX, leading to p53 activation. However, the structural basis of stress-induced p53 activation remains poorly understood because of the paucity of technical means to produce site-specifically phosphorylated MDM2 and MDMX proteins for biochemical and biophysical studies. Herein, we report total chemical synthesis, via native chemical ligation, and functional characterization of (24-108)MDMX and its Tyr99-phosphorylated analog with respect to their ability to interact with a panel of p53-derived peptide ligands and PMI, a p53-mimicking but more potent peptide antagonist of MDMX, using FP and surface plasmon resonance techniques. Phosphorylation of MDMX at Tyr99 weakens peptide binding by approximately two orders of magnitude. Comparative X-ray crystallographic analyses of MDMX and of pTyr99 MDMX in complex with PMI as well as modeling studies reveal that the phosphate group of pTyr99 imposes extensive steric clashes with the C-terminus of PMI or p53 peptide and induces a significant lateral shift of the peptide ligand, contributing to the dramatic decrease in the binding affinity of MDMX for p53. Because DNA damage activates c-Abl tyrosine kinase that phosphorylates MDMX at Tyr99, our findings afford a rare glimpse at the structural level of how stress-induced MDMX phosphorylation dislodges p53 from the inhibitory complex and activates it in response to DNA damage.
| S-EPMC5470632 | biostudies-literature
Project description:N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic messenger RNA (mRNA), and affects almost every stage of the mRNA life cycle. The YTH-domain proteins can specifically recognize m6A modification to control mRNA maturation, translation and decay. m6A can also alter RNA structures to affect RNA-protein interactions in cells. Here, we show that m6A increases the accessibility of its surrounding RNA sequence to bind heterogeneous nuclear ribonucleoprotein G (HNRNPG). Furthermore, HNRNPG binds m6A-methylated RNAs through its C-terminal low-complexity region, which self-assembles into large particles in vitro. The Arg-Gly-Gly repeats within the low-complexity region are required for binding to the RNA motif exposed by m6A methylation. We identified 13,191 m6A sites in the transcriptome that regulate RNA-HNRNPG interaction and thereby alter the expression and alternative splicing pattern of target mRNAs. Low-complexity regions are pervasive among mRNA binding proteins. Our results show that m6A-dependent RNA structural alterations can promote direct binding of m6A-modified RNAs to low-complexity regions in RNA binding proteins.
| S-EPMC5449601 | biostudies-literature
Project description:Mmi1 is an essential RNA-binding protein in the fission yeast Schizosaccharomyces pombe that eliminates meiotic transcripts during normal vegetative growth. Mmi1 contains a YTH domain that binds specific RNA sequences, targeting mRNAs for degradation. The YTH domain of Mmi1 uses a noncanonical RNA-binding surface that includes contacts outside the conserved fold. Here, we report that an N-terminal extension that is proximal to the YTH domain enhances RNA binding. Using X-ray crystallography, NMR, and biophysical methods, we show that this low-complexity region becomes more ordered upon RNA binding. This enhances the affinity of the interaction of the Mmi1 YTH domain with specific RNAs by reducing the dissociation rate of the Mmi1-RNA complex. We propose that the low-complexity region influences RNA binding indirectly by reducing dynamic motions of the RNA-binding groove and stabilizing a conformation of the YTH domain that binds to RNA with high affinity. Taken together, our work reveals how a low-complexity region proximal to a conserved folded domain can adopt an ordered structure to aid nucleic acid binding.
| S-EPMC6005420 | biostudies-literature