A short peptide derived from late embryogenesis abundant proteins enhances acid tolerance in Escherichia coli via modulation of two‐component regulatory systems

Late embryogenesis abundant (LEA) proteins are responsible for facilitating tolerance to various environmental stresses across diverse organisms. Group 3 LEA proteins are characterised by the presence of 11‐mer amino acid motifs, which inspired the design of short peptides with similar protective functions. Here, we designed a LEA peptide variant (LEA‐K) and evaluated its acid tolerance capacity in Escherichia coli BL21 (DE3) at pH4. Expression of LEA‐K peptide improved the bacterial viability under acidic stress, suggesting its protective functions. To explore the molecular mechanism of such tolerance, we combined the RNA‐sequencing (RNA‐Seq) technique and molecular docking simulations. Transcriptome analysis identified 283 differentially expressed genes (DEGs), and revealed metabolic reprogramming and activation of stress‐related pathways, including proton pumping, biofilm formation, and stress responsive systems. Functional enrichment analysis suggested a key role of two‐component regulatory systems (TCSs) such as reactive chlorine species (RCS), sensor histidine kinase BtsS/transcriptional regulatory protein BtsR, and DNA‐binding dual transcriptional regulator OmpR/sensor histidine kinase EnvZ. Protein–peptide docking simulations indicated potential interactions between LEA‐K and these TCSs, suggesting a mechanistic basis of the observed transcriptional modulation. These findings propose previously unknown functional roles for LEA peptides, not only acting as molecular shields but also as signal‐transducing modulators. This work expands our understanding of stress tolerance mechanisms and presents a new avenue for engineering stress‐resilient bacterial systems.