Mycobacterium tuberculosis RbpA protein is a new type of transcriptional activator that stabilizes the ΣA-containing RNA polymerase holoenzyme

RbpA is an RNA polymerase (RNAP)-binding protein whose presence increases the tolerance levels of Mycobacteria to the first-line anti-tuberculosis drug rifampicin by an unknown mechanism. Here, we show that the role of Mycobacterium tuberculosis RbpA in resistance is indirect because it does not affect the sensitivity of RNAP to rifampicin while it stimulates transcription controlled by the housekeeping Sigma(A)-factor. The transcription regulated by the stress-related Sigma(F) was not affected by RbpA. The binding site of RbpA maps to the RNAP beta subunit Sandwich-Barrel Hybrid Motif, which has not previously been described as an activator target and does not overlap the rifampicin binding site. Our data suggest that RbpA modifies the structure of the core RNAP, increases its affinity for Sigma(A) and facilitates the assembly of the transcriptionally competent promoter complexes. We propose that RbpA is an essential partner which advantages Sigma(A) competitiveness for core RNAP binding with respect to the alternative Sigma factors. The RbpA-driven stimulation of the housekeeping gene expression may help Mycobacteria to tolerate high rifampicin levels and to adapt to the stress conditions during infection.