During proteotoxic stress, bacteria maintain critical processes like DNA replication while removing misfolded proteins, which are degraded by the Lon protease. Here, we show that in Caulobacter crescentus Lon controls deoxyribonucleoside triphosphate (dNTP) pools during stress through degradation of the transcription factor CcrM. Elevated dNTP/nucleotide triphosphate (NTP) ratios in Δlon cells protects them from deletion of otherwise essential deoxythymidine triphosphate (dTTP)-producing pathways and shields them from hydroxyurea-induced loss of dNTPs. Increased dNTP production in Δlon results from higher expression of ribonucleotide reductase driven by increased CcrM. We show that misfolded proteins can stabilize CcrM by competing for limited protease and that Lon-dependent control of dNTPs improves fitness during protein misfolding conditions. We propose that linking dNTP production with availability of Lon allows Caulobacter to maintain replication capacity when misfolded protein burden increases, such as during rapid growth. Because Lon recognizes misfolded proteins regardless of the stress, this mechanism allows for response to a variety of unanticipated conditions.

在蛋白毒性应激期间，细菌会维持 DNA 复制等关键过程，同时去除被 Lon 蛋白酶降解的错误折叠蛋白质。在这里，我们展示了在Caulobacter crescentus 中， Lon 在压力期间通过转录因子 CcrM 的降解控制脱氧核糖核苷三磷酸 (dNTP) 池。Δ lon细胞中dNTP/核苷酸三磷酸 (NTP) 比率升高可保护它们免受其他必需的脱氧胸苷三磷酸 (dTTP) 生成途径的缺失，并保护它们免受羟基脲诱导的 dNTP 损失。在 Δ lon 中增加 dNTP 产量由增加的 CcrM 驱动的核糖核苷酸还原酶的更高表达的结果。我们表明错误折叠的蛋白质可以通过竞争有限的蛋白酶来稳定 CcrM，并且 dNTP 的 Lon 依赖性控制可以提高蛋白质错误折叠条件下的适应性。我们建议将 dNTP 生产与 Lon 的可用性联系起来，允许Caulobacter在错误折叠的蛋白质负荷增加时保持复制能力，例如在快速生长期间。因为无论压力如何，Lon 都能识别错误折叠的蛋白质，因此这种机制允许对各种意外情况做出反应。