Protein aggregation as a bistable switch in bacterial cell fate: from adaptive dormancy to cytotoxic death

Protein aggregation has traditionally been considered a hallmark of proteostasis disruption and cellular dysfunction. However, recent studies have revealed that bacterial protein aggregation is not merely a passive consequence of stress-induced damage but may represent a dynamic component of cellular adaptation. Under adverse conditions, reversible protein condensation and aggregation have been associated with bacterial dormancy, persistence, and the viable but non-culturable (VBNC) state, whereas excessive and irreversible aggregation may contribute to loss of cellular function and bacterial death. Nevertheless, whether protein aggregation serves as a primary determinant of bacterial cell fate or reflects a consequence of broader physiological changes remains an important unresolved question. In this review, we summarize current advances in understanding bacterial protein aggregation, including the roles of liquid-liquid phase separation (LLPS), protein quality control systems, ATP-dependent proteostasis regulation, and aggregate maturation. We discuss how stress-induced alterations in proteostasis networks influence bacterial survival, aging, persistence, and antibiotic tolerance. Available evidence supports a working model whereby the physicochemical properties of protein aggregates may dictate ultimate bacterial cell fate. Nevertheless, the causal link between condensate phase behavior, aggregate material characteristics, and cell fate decisions remains to be thoroughly validated, even though emerging technologies including live single-molecule cell imaging and quantitative analytical tools have greatly advanced our mechanistic understanding of the dynamic progression of bacterial protein aggregation. Finally, we discuss the therapeutic potential and challenges of targeting bacterial proteostasis and aggregation pathways to combat persistent and multidrug-resistant pathogens. A deeper mechanistic understanding of how protein aggregation balances adaptation and toxicity may reveal new vulnerabilities within bacterial survival strategies.