One of the important determinants of virulence of Mycobacterium tuberculosis is adaptation to adverse conditions encountered in the host cells. The ability of Mycobacterium to successfully adapt to stress conditions is brought about by the expression of specific regulons effected by a repertoire of σ factors. The induction and availability of σ factors in response to specific stimuli is governed by a complex regulatory network comprising a number of proteins, including σ factors themselves. A serine–threonine protein kinase‐mediated signaling pathway adds another dimension to the mycobacterial σ factor regulatory network. This review highlights the recent advances in understanding mycobacterial σ factors, their regulation and contribution to bacterial pathogenesis.

Serine/threonine protein kinases (STPKs) are known to act as sensors of environmental signals that thereby regulate developmental changes and host pathogen interactions. In this study, we carried out comparative genome analysis of six completely sequenced pathogenic and nonpathogenic mycobacterial species to systematically characterize the STPK complement of mycobacterium. Our analysis revealed that while Mycobacterium tuberculosis strains have 11 conserved kinases, this number varies from 4 to 24 in other mycobacterial species. pknA, an essential STPK encoding gene, was found to be truncated in the initial analysis of M. avium subsp. paratuberculosis (Map) and M. tuberculosis C genomes. However, resequencing of pknA gene in Map confirmed that the truncation was due to a sequencing error. The conservation of division and cell wall gene cluster involved in cell envelope biosynthesis and cell division, in the vicinity of pknL locus, implicates a possible role of PknL in cell division and envelop biosynthesis. We identified a cyclophilin domain as part of a mycobacterial kinase in Map that suggests a plausible regulation of cyclophilins by phosphorylation. The co-inheritance of pknA, pknB, pknG, and pknL loci across genomes and some unique repertoire of pathogen-specific kinases such as pknI and pknJ of Mtb complex suggest similitude and divergence between pathogenic and nonpathogenic signaling. This study would add another dimension toward identification of physiological substrates and thereby function, while resolving the existing complexities in signaling network between the two domains of life, pathogen and nonpathogen.

The alternative sigma factors are regulated by a phosphorylation‐mediated signal transduction cascade involving anti‐sigma factors and anti‐anti‐sigma factors. The proteins regulating Mycobacterium tuberculosis sigma factor F (SigF), anti‐SigF and anti‐anti‐SigF have been identified, but the factors catalyzing phosphorylation–dephosphorylation have not been well established. We identified a distinct pathogenic species‐specific multidomain protein, Rv1364c, in which the components of the entire signal transduction cascade for SigF regulation appear to be encoded in a single polypeptide. Sequence analysis of M. tuberculosis Rv1364c resulted in the prediction of various domains, namely a phosphatase (RsbU) domain, an anti‐SigF (RsbW) domain, and an anti‐anti‐SigF (RsbV) domain. We report that the RsbU domain of Rv1364c bears all the conserved features of the PP2C‐type serine/threonine phosphatase family, whereas its RsbW domain has certain substitutions and deletions in regions important for ATP binding. Another anti‐SigF protein in M. tuberculosis, UsfX (Rv3287c), shows even more unfavorable substitutions in the kinase domain. Biochemical assay with the purified RsbW domain of Rv1364c and UsfX showed the loss of ability of autophosphorylation and phosphotransfer to cognate anti‐anti‐SigF proteins or artificial substrates. Both the Rv1364c RsbW domain and UsfX protein display very weak binding with fluorescent ATP analogs, despite showing functional interactions characteristic of anti‐SigF proteins. In view of conservation of specific interactions with cognate sigma and anti‐anti‐sigma factor, the loss of kinase activity of Rv1364c and UsfX appears to form a missing link in the phosphorylation‐dependent interaction involved in SigF regulation in Mycobacterium.