Distinct metabolic states of a cell guide alternate fates of mutational buffering through altered proteostasis

• Published in: Nature communications Vol. 11; no. 1; pp. 2926 - 15
• Main Authors: Verma, Kanika, Saxena, Kanika, Donaka, Rajashekar, Chaphalkar, Aseem, Rai, Manish Kumar, Shukla, Anurag, Zaidi, Zainab, Dandage, Rohan, Shanmugam, Dhanasekaran, Chakraborty, Kausik
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.06.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 49/31; 49/39; 631/45/470/1981; 631/92/470; 82/47; 82/58; 82/80; 82/83; Buffers; Chaperones; E coli; Escherichia coli - genetics; Escherichia coli - metabolism; Folding; Homeostasis; Humanities and Social Sciences; Metabolism; Metabolites; Metabolome - genetics; Molecular Biology; Molekylärbiologi; multidisciplinary; Mutation; Mutation - genetics; Osmotic Pressure - physiology; Plastic foam; Protein Folding; Protein turnover; Proteins; Proteostasis - genetics; Proteostasis - physiology; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16804-6

Metabolic changes alter the cellular milieu; can this also change intracellular protein folding? Since proteostasis can modulate mutational buffering, if change in metabolism has the ability to change protein folding, arguably, it should also alter mutational buffering. Here we find that altered cellular metabolic states in E. coli buffer distinct mutations on model proteins. Buffered-mutants have folding problems in vivo and are differently chaperoned in different metabolic states. Notably, this assistance is dependent upon the metabolites and not on the increase in canonical chaperone machineries. Being able to reconstitute the folding assistance afforded by metabolites in vitro, we propose that changes in metabolite concentrations have the potential to alter protein folding capacity. Collectively, we unravel that the metabolite pools are bona fide members of proteostasis and aid in mutational buffering. Given the plasticity in cellular metabolism, we posit that metabolic alterations may play an important role in cellular proteostasis. Changes in osmotic homeostasis alter metabolites and therefore chemical milieu of the cells. Here, the authors show that altering metabolites in E. coli also change the cellular capacity for buffering mutations that impair protein folding and influences proteostasis irrespective of molecular chaperones