ExsA

ExsA is a transcriptional activator in Pseudomonas aeruginosa that controls the expression of the bacterium’s Type III secretion system (T3SS). It belongs to the AraC family of transcriptional regulators and functions by directly binding to promoter regions of T3SS regulon genes to initiate transcription. ExsA activates a set of operons and effector genes, including those in the exsCEBA operon and key virulence factors such as exoS, exoT, exoU, and exoY, thereby enabling the assembly and deployment of the T3SS.

Regulation of ExsA activity is orchestrated by the ExsC-ExsD-ExsE regulatory module. In non-inducing conditions, ExsD binds ExsA and inhibits transcription of T3SS genes. ExsC can bind ExsD, releasing ExsA from inhibition, while ExsE binds ExsC and prevents ExsC from alleviating ExsD repression. Upon signals associated with host environments or other T3SS-inducing conditions, ExsE is secreted through the T3SS, freeing ExsC to sequester ExsD and thereby allowing ExsA to activate transcription. This regulatory cascade links environmental cues to the controlled expression of the T3SS.

Structurally, ExsA operates as a dimeric transcriptional activator within the AraC family and requires promoter binding to initiate transcription of T3SS components. Its activity is essential for robust T3SS expression and contributes to the cytotoxicity and virulence of P. aeruginosa in infection models. While best characterized in P. aeruginosa, ExsA-like regulators and their regulatory circuits are found in other bacteria with T3SS, reflecting a conserved strategy for tightly regulating virulence gene expression.