Discovery and characterization of a second BlaRI-type two-component signaling system in Mycobacterium abscessus

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Pathogens utilize a diverse set of signal transduction mechanisms to respond to host-derived stresses, with phosphotransfer-mediated two component systems (TCS) playing key roles in virulence factor regulation. Staphylococcus aureus encodes an alternative protease-mediated TCS prototype known as BlaRI involved in inducible β-lactam resistance. BlaR senses extracellular β-lactams, leading to activation of a cytoplasmic protease domain able to cleave DNA-bound BlaI dimers, de-repressing blaRI and blaZ (β-lactamase). The two known mycobacterial BlaRI-type systems in M. tuberculosis (Mtb) and M. abscessus ( Mab ) are characterized by BlaR orthologs with conserved zinc metalloprotease domain but lacking an extracellular β-lactam binding domain. BlaIR Mtb and BlaIR Mab (renamed BlaIR to reflect inverted genomic organization) regulate β-lactamase expression ( Mtb only) and respiration (both Mtb and Mab ). In this study, we have identified a second BlaRI-type system in Mab , MAB_4287-4288 (BlaIR2). Using RT-PCR and EMSA, we established that BlaIR2 Mab is encoded within a five gene operon, a unique characteristic in BlaRI-type systems, and is auto-regulatory. Identification of putative BlaI2 Mab binding motifs revealed a predicted regulon comprised of several genes involved in respiration, with some overlap with the BlaI1 Mab regulon. Finally, our data demonstrated that BlaIR2 Mab was also induced by the respiration inhibitor clofazimine (CFZ) similarly to BlaIR1 Mab , with evidence of possible crosstalk between BlaRI systems. Overall, this study established MAB_4287-4288 (BlaIR2 Mab ) as a second BlaRI-type system in Mab , whose role may overlap or intersect that of BlaRI1 Mab . However, the activation mechanism and full role of BlaIR2 Mab in Mab stress responses and pathogenesis remains to be elucidated.

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