Understanding the Streptomyces albulus response to low-pH stress at the interface of physiology and transcriptomics

Abstract

Streptomyces albulus is a well-established cell factory for ε-poly-L-lysine (ε-PL) production. It has been reported that ε-PL biosynthesis is strictly regulated by pH and that ε-PL can accumulate at approximately pH 4.0, which is outside of the general pH range for natural product production by Streptomyces species. However, how S. albulus responds to low pH is not clear. In this study, we attempted to explore the response of S. albulus to low-pH stress at the physiological and global gene transcription levels. At the physiological level, S. albulus maintained intracellular pH homeostasis at ~pH 7.5, increased the unsaturated fatty acid ratio, extended the fatty acid chain length, enhanced ATP accumulation, increased H⁺-ATPase activity, and accumulated the basic amino acids L-lysine and L-arginine. At the global gene transcription level, carbohydrate metabolism, oxidative phosphorylation, macromolecule protection and repair, and the acid tolerance system were found to be involved in combating low-pH stress. Finally, we preliminarily evaluated the effect of the acid tolerance system and cell membrane fatty acid synthesis on low-pH tolerance via gene manipulation. This work provides new insight into the adaptation mechanism of Streptomyces to low-pH stress and a new opportunity for constructing robust S. albulus strains for ε-PL production. KEY POINTS: • S. albulus consistently remained pH _i at ~7.4 regardless of the environmental pH. • S. albulus combats low-pH stress by modulating lipid composition of cell membrane. • Overexpression of cfa in S. albulus could improve low-pH tolerance and ɛ-PL titer.

Keywords: Low-pH stress; Streptomyces; Tolerance mechanism; Transcriptomic analysis.