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            The pathogenic mechanisms of many diseases are well understood at the molecular level, but there are prevalent syndromes associated with pathogenic signaling, such as diabetes and chronic inflammation, where our understanding is more limited. Here, we report that pathogenic signaling suppresses the mobility of a spectrum of proteins that play essential roles in cellular functions known to be dysregulated in these chronic diseases. The reduced protein mobility, which we call proteolethargy, was linked to cysteine residues in the affected proteins and signaling-related increases in excess reactive oxygen species. Diverse pathogenic stimuli, including hyperglycemia, dyslipidemia, and inflammation, produce similar reduced protein mobility phenotypes. We propose that proteolethargy is an overlooked cellular mechanism that may account for various pathogenic features of diverse chronic diseases.more » « lessFree, publicly-accessible full text available January 1, 2026
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            Henninger, Jonathan E.; Oksuz, Ozgur; Shrinivas, Krishna; Sagi, Ido; LeRoy, Gary; Zheng, Ming M.; Andrews, J. Owen; Zamudio, Alicia V.; Lazaris, Charalampos; Hannett, Nancy M.; et al (, Cell)
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            Klein, Isaac A.; Boija, Ann; Afeyan, Lena K.; Hawken, Susana Wilson; Fan, Mengyang; Dall'Agnese, Alessandra; Oksuz, Ozgur; Henninger, Jonathan E.; Shrinivas, Krishna; Sabari, Benjamin R.; et al (, Science)null (Ed.)The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.more » « less
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