Protein aggregates encode epigenetic memory of stressful encounters in individual Escherichia coli cells

摘要

Protein misfolding and aggregation are typically perceived as inevitable and detrimental processes tied to a stress- or age-associated decline in cellular proteostasis. A careful reassessment of this paradigm in the E . coli model bacterium revealed that the emergence of intracellular protein aggregates (PAs) was not related to cellular aging but closely linked to sublethal proteotoxic stresses such as exposure to heat, peroxide, and the antibiotic streptomycin. After removal of the proteotoxic stress and resumption of cellular proliferation, the polarly deposited PA was subjected to limited disaggregation and therefore became asymmetrically inherited for a large number of generations. Many generations after the original PA-inducing stress, the cells inheriting this ancestral PA displayed a significantly increased heat resistance compared to their isogenic, PA-free siblings. This PA-mediated inheritance of heat resistance could be reproduced with a conditionally expressed, intracellular PA consisting of an inert, aggregation-prone mutant protein, validating the role of PAs in increasing resistance and indicating that the resistance-conferring mechanism does not depend on the origin of the PA. Moreover, PAs were found to confer robustness to other proteotoxic stresses, as imposed by reactive oxygen species or streptomycin exposure, suggesting a broad protective effect. Our findings therefore reveal the potential of intracellular PAs to serve as long-term epigenetically inheritable and functional memory elements, physically referring to a previous cellular insult that occurred many generations ago and meanwhile improving robustness to a subsequent proteotoxic stress. The latter is presumably accomplished through the PA-mediated asymmetric inheritance of protein quality control components leading to their specific enrichment in PA-bearing cells. Author summary Since accurate protein folding is crucial for cellular viability, misfolded and aggregated proteins have typically been thought of as detrimental structures with potentially harmful physiological effects. In this report, we show that this general paradigm does not appear to hold in the model bacterium Escherichia coli . We find that the emergence of protein aggregates is mainly linked to sublethal, proteotoxic exposures (e.g., heat stress) and that asymmetric partitioning of these aggregates among daughter cells may have benefits beyond mere waste disposal. In fact, cells that inherited an ancestral protein aggregate (formed during stress exposure many generations before) were better able to cope with subsequent exposure to proteotoxic stress. Our observations therefore reveal the existence of stress-induced, long-term, and protein aggregate–mediated “memory” in prokaryotes and highlight the potential role of protein aggregation in aiding cellular survival and adaptation in fluctuating environments.