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Material properties of biomolecular condensates regulates RNA splicing and tumorigenesis

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE122308 | GEO | 2020/05/06

REPOSITORIES: GEO

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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.

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Material properties of biomolecular condensates regulates RNA splicing and tumorigenesis

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