An adaptive biomolecular condensation response is conserved across environmentally divergent species
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ABSTRACT:
PROVIDER: PRJNA981544 | ENA |
REPOSITORIES: ENA
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Project description:Cellular responses to maladaptive environmental changes—stresses—allow for organismal adaptation to diverse and dynamic conditions. Across the tree of life, cells upregulate a highly conserved transcriptional program in response to so-called proteotoxic stresses such as heat shock. Correspondingly, in eukaryotes, these stresses induce the formation of biomolecular condensates, clusters of mRNA and protein which are referred to as stress granules under severe stress. However, major questions remain about this stress-induced response. How conserved is the condensation response relative to the transcriptional response? How does it vary across environmental niches, and to what extent does it correspond with the conserved transcriptional response? To answer these fundamental questions, we studied the growth, transcriptional, and condensation heat-induced stress responses in three fungal species adapted to thrive in different thermal environments: cryophilic S. kudriavzevii, mesophilic S. cerevisiae, and thermotolerant K. marxianus. Here we show that transcriptional heat shock responses track each species’ evolved temperature range of growth. Further, orthologous proteins—including poly(A)-binding protein, Pab1, a core marker of stress granules—form condensates in vivo at temperatures systematically tuned to the temperature at which the organisms activate the transcriptional heat shock response and slow their growth. In vitro, purified Pab1 from each species condenses autonomously at niche-specific temperatures. Homologous mutations in Pab1 cause similar shifts in relative condensation temperature across species, and crucially, mutations which suppress condensation in vitro also reduce fitness during heat stress. Our findings indicate that stress-induced protein condensation is adaptive, conserved, integrated with the growth and transcriptional responses, and tuned to features of the cellular and organismal environment to initiate at niche-specific levels.
2023-07-31 | GSE234499 | GEO
Project description:Cells must sense and respond to sudden maladaptive environmental changes—stresses—to survive and thrive. Across eukaryotes, stresses such as heat shock trigger conserved responses: growth arrest, a specific transcriptional response, and biomolecular condensation of protein and mRNA into structures known as stress granules under severe stress. The composition, formation mechanism, adaptive significance, and even evolutionary conservation of these condensed structures remain enigmatic. Here we provide an unprecedented view into stress-triggered condensation, its evolutionary conservation and tuning, and its integration into other well-studied aspects of the stress response. Using three morphologically near-identical budding yeast species adapted to different thermal environments and diverged by up to 100 million years, we show that proteome-scale biomolecular condensation is tuned to species-specific thermal niches, closely tracking corresponding growth and transcriptional responses. In each species, poly(A)-binding protein—a core marker of stress granules—condenses in isolation at species-specific temperatures, with conserved molecular features and conformational changes modulating condensation. From the ecological to the molecular scale, our results reveal previously unappreciated levels of evolutionary selection in the eukaryotic stress response, while establishing a rich, tractable system for further inquiry.
2024-03-03 | PXD044702 | Pride
Project description:Cells must sense and respond to sudden maladaptive environmental changes—stresses—to survive and thrive. Across eukaryotes, stresses such as heat shock trigger conserved responses: growth arrest, a specific transcriptional response, and biomolecular condensation of protein and mRNA into structures known as stress granules under severe stress. The composition, formation mechanism, adaptive significance, and even evolutionary conservation of these condensed structures remain enigmatic. Here we provide an unprecedented view into stress-triggered condensation, its evolutionary conservation and tuning, and its integration into other well-studied aspects of the stress response. Using three morphologically near-identical budding yeast species adapted to different thermal environments and diverged by up to 100 million years, we show that proteome-scale biomolecular condensation is tuned to species-specific thermal niches, closely tracking corresponding growth and transcriptional responses. In each species, poly(A)-binding protein—a core marker of stress granules—condenses in isolation at species-specific temperatures, with conserved molecular features and conformational changes modulating condensation. From the ecological to the molecular scale, our results reveal previously unappreciated levels of evolutionary selection in the eukaryotic stress response, while establishing a rich, tractable system for further inquiry.
2024-03-03 | PXD044970 | Pride
Project description:Cells must sense and respond to sudden maladaptive environmental changes-stresses-to survive and thrive. Across eukaryotes, stresses such as heat shock trigger conserved responses: growth arrest, a specific transcriptional response, and biomolecular condensation of protein and mRNA into structures known as stress granules under severe stress. The composition, formation mechanism, adaptive significance, and even evolutionary conservation of these condensed structures remain enigmatic. Here we provide an unprecedented view into stress-triggered condensation, its evolutionary conservation and tuning, and its integration into other well-studied aspects of the stress response. Using three morphologically near-identical budding yeast species adapted to different thermal environments and diverged by up to 100 million years, we show that proteome-scale biomolecular condensation is tuned to species-specific thermal niches, closely tracking corresponding growth and transcriptional responses. In each species, poly(A)-binding protein-a core marker of stress granules-condenses in isolation at species-specific temperatures, with conserved molecular features and conformational changes modulating condensation. From the ecological to the molecular scale, our results reveal previously unappreciated levels of evolutionary selection in the eukaryotic stress response, while establishing a rich, tractable system for further inquiry.
| S-EPMC10402146 | biostudies-literature
Project description:Cells must sense and respond to sudden maladaptive environmental changes-stresses-to survive and thrive. Across eukaryotes, stresses such as heat shock trigger conserved responses: growth arrest, a specific transcriptional response, and biomolecular condensation of protein and mRNA into structures known as stress granules under severe stress. The composition, formation mechanism, adaptive significance, and even evolutionary conservation of these condensed structures remain enigmatic. Here we provide a remarkable view into stress-triggered condensation, its evolutionary conservation and tuning, and its integration into other well-studied aspects of the stress response. Using three morphologically near-identical budding yeast species adapted to different thermal environments and diverged by up to 100 million years, we show that proteome-scale biomolecular condensation is tuned to species-specific thermal niches, closely tracking corresponding growth and transcriptional responses. In each species, poly(A)-binding protein-a core marker of stress granules-condenses in isolation at species-specific temperatures, with conserved molecular features and conformational changes modulating condensation. From the ecological to the molecular scale, our results reveal previously unappreciated levels of evolutionary selection in the eukaryotic stress response, while establishing a rich, tractable system for further inquiry.
| S-EPMC11009240 | biostudies-literature
Project description:Clathrin-mediated endocytosis is an essential cellular internalisation pathway involving the dynamic assembly of clathrin and accessory proteins to form membrane-bound vesicles. The evolutionarily ancient TSET/TPLATE complex (TPC) plays an essential, but not well-defined role in endocytosis in plants. Here, we show that two highly disordered TPC subunits, AtEH1 and AtEH2 function as scaffolds to drive biomolecular condensation of the complex. These condensates specifically nucleate on the plasma membrane through interactions with anionic phospholipids, and facilitate the dynamic recruitment and assembly of clathrin, early-, and late-stage endocytic accessory proteins. Importantly, clathrin forms ordered assemblies within the condensate environment. Biomolecular condensation therefore acts to promote dynamic protein assemblies throughout clathrin-mediated endocytosis. Furthermore, the disordered region sequence properties of AtEH1 regulate the material properties of the endocytic condensates in vivo. Alteration of the material properties influences endocytosis dynamics, and thereby impairs environmental adaption. In summary, our findings reveal how collective interactions shape endocytosis.
2023-12-07 | PXD045068 | Pride
Project description:NUP98-fusion proteins cause leukemia via unknown molecular mechanisms. All NUP98-fusion proteins share an intrinsically disordered region (IDR) featuring >35 repeats of Phenylalanine-Glycine (FG) in the NUP98 N-terminus. Conversely, C-terminal NUP98-fusion partners often have critical functions in gene control. Given these structural features we hypothesized that mechanisms of oncogenic transformation by NUP98-fusion proteins are hard-wired in their protein interactomes. Affinity purification coupled to mass spectrometry and confocal imaging of five distinct NUP98-fusion proteins revealed that conserved interactors were enriched for proteins involved in biomolecular condensation and that they co-localized with NUP98-fusion proteins in nuclear puncta. We developed biotinylated isoxazole-mediated condensome mass spectrometry (biCon-MS) to show that NUP98-fusion proteins alter the global composition of biomolecular condensates. An artificial FG-repeat-containing fusion protein phenocopied the nuclear localization patterns of NUP98-fusion proteins and their capability to drive oncogenic gene expression programs. Thus, we propose that IDR-containing fusion proteins uniquely combine biomolecular condensation with transcriptional control to induce cancer.
2020-12-23 | PXD022518 | Pride
Project description:NUP98-fusion proteins cause acute myeloid leukemia via unknown molecular mechanisms. All NUP98-fusion proteins share an intrinsically disordered region (IDR) featuring >35 repeats of Phenylalanine-Glycine (FG) in the NUP98 N-terminus. Conversely, different C-terminal NUP98-fusion partners are often transcriptional and epigenetic regulators. Given these structural features we hypothesized that mechanisms of oncogenic transformation by NUP98-fusion proteins are hard-wired in their protein interactomes. Affinity purification coupled to mass spectrometry of five distinct NUP98-fusion proteins revealed a conserved set of interactors that was highly enriched for proteins involved in biomolecular condensation. We developed biotinylated isoxazole-mediated condensome mass spectrometry (biCon-MS) to show that NUP98-fusion proteins alter the global composition of biomolecular condensates. In addition, an artificial FG-repeat containing fusion protein was able to phenocopy the induction of leukemic gene expression as mediated by NUP98-KDM5A. Thus, we propose that IDR-containing fusion proteins have evolved to uniquely combine biomolecular condensation with gene control to induce cancer.
2021-02-16 | GSE159037 | GEO
Project description:It remains largely unclear how material properties of biomolecular condensates impact physiological and pathological processes such as cancer. Here we show that AKAP95, a nuclear protein involved in gene regulation, plays an important role in tumorigenesis through directly regulating mRNA splicing. We show that AKAP95, through an intrinsic disordered region (IDR), forms liquid-like droplets in vitro and dynamic foci in nucleus. We have also identified key residues in IDR whose mutations to different residues perturb AKAP95 condensation in opposite directions. Importantly, the biological activity of AKAP95 in splice regulation is affected by either disruption of liquid condensation or enhancing the gelation of the assembly. We then show that the ability of AKAP95 in overcoming oncogene-induced senescence requires AKAP95 in an appropriate window of liquidity. These results thus link phase separation to tumorigenesis and uncover an important role of regulating the material property of protein condensates in disease including cancer.
2020-05-06 | GSE122308 | GEO
Project description:Optimum protein function and biochemical activity critically depends on water availability, because solvent thermodynamics drive protein folding and macromolecular interactions. Reciprocally, macromolecules restrict the movement of “structured” water molecules within their hydration layers, reducing the available “free” bulk solvent and therefore the total thermodynamic potential energy of water, or water potential. Within concentrated macromolecular solutions like the cytosol, we found modest changes in temperature greatly impact the water potential, and are counteracted by opposing changes in osmotic strength. Remarkably, this duality of temperature and osmotic strength allows simple manipulations of solvent thermodynamics to prevent cell death upon extreme cold or heat shock. Physiologically, cells must sustain their activity against fluctuating temperature, pressure and osmotic strength that impact water availability within seconds. Yet, established mechanisms of water homeostasis act over much slower timescales, so we postulated the existence of a rapid compensatory response. We find this function is performed by water potential-driven changes in macromolecular assembly, particularly biomolecular condensation of intrinsically-disordered proteins. Formation or dissolution of biomolecular condensates liberates and captures free water, respectively, quickly counteracting thermal or osmotic perturbations of water potential, which in consequence is robustly buffered in the cytoplasm. Our results indicate biomolecular condensation constitutes an intrinsic biophysical feedback response that rapidly compensates for intracellular osmotic and thermal fluctuations. We suggest preserving water availability within the concentrated cytosol is an overlooked evolutionary driver of protein (dis)order and function.
2023-09-22 | PXD044481 | Pride