The intracellular space is a crowded environment where macromolecules perform distinct tasks despite pervasive "non-specific" interactions. Whether these interactions are functionally relevant and how they influence cellular organization remains unclear. Here, we developed QuPID-MS, which measures the propensity of proteins to phase separate in native cell extracts proteome-wide. We find that weak interactions drive condensation of half of the proteome in a crowding- and temperature-dependent manner and we present evidence that this proteome demixing occurs in cells. Importantly, protein condensation properties are conserved and broadly change when cells adapt to new environments, demonstrating that weak interactions are regulated and linked to function. Indeed, condensation of the growth regulator TORC1 coincides with its rapid inactivation, while high solubility of the stress-activated Hog1 ensures its activity across conditions. We thus uncover a fundamental organizing principle that allows tuning of cell growth to environmental fluctuations while ensuring other processes function robustly despite perturbations.
Accurate predictions of transcriptomic responses to genetic perturbations could unlock our understanding of gene functions and regulatory networks. While a growing number of methods and benchmarks target this task, existing evaluations focus on mean expression accuracy alone. Thi…
Glioblastoma (GBM) cell states reflect spatial microenvironmental interactions. Here, using COMET spatial proteomics and RNAscope across multiregional human GBM tissue, spanning tumor cores with pseudopalisading regions, infiltrative margins and peripheral regions, together with…
ABSTRACT Sensory abnormalities are core features of neurodevelopmental disorders, including autism. Although interneuron dysfunction is hypothesized to contribute to these deficits, the underlying mechanisms remain unclear. Here, we demonstrate that mTORC1 dysregulation in parval…
CD19 targeted chimeric antigen receptor (CAR) T cell therapy achieves high initial response rates in B cell acute lymphoblastic leukemia (B ALL), yet half of patients relapse within one year. Pre-infusion product composition decoded by single-cell RNA sequencing (scRNA-seq) carri…
Epilepsy affects approximately 30% of individuals with autism spectrum disorder (ASD). Consistent with these observations, while PRICKLE mutations are primarily linked with epilepsy, there is an enrichment of pathogenic DNA sequence variants in PRICKLE genes carried by individual…
The noradrenergic locus coeruleus (LC) and the cholinergic nucleus basalis of Meynert (nBM) are key hubs of ascending neuromodulatory systems that shape large-scale brain dynamics. However, the behavioral relevance of the structural and functional connectivity between these nucle…