Alternative sigma factors and their roles in bacterial virulence

Abstract

Sigma factors provide promoter recognition specificity to RNA polymerase holoenzyme, contribute to DNA strand separation, and then dissociate from the core enzyme following transcription initiation. As the regulon of a single sigma factor can be composed of hundreds of genes, sigma factors can provide effective mechanisms for simultaneously regulating expression of large numbers of prokaryotic genes. One newly emerging field is identification of the specific roles of alternative sigma factors in regulating expression of virulence genes and virulence-associated genes in bacterial pathogens. Virulence genes encode proteins whose functions are essential for the bacterium to effectively establish an infection in a host organism. In contrast, virulence-associated genes can contribute to bacterial survival in the environment and therefore may enhance the capacity of the bacterium to spread to new individuals or to survive passage through a host organism. As alternative sigma factors have been shown to regulate expression of both virulence and virulence-associated genes, these proteins can contribute both directly and indirectly to bacterial virulence. Sigma factors are classified into two structurally unrelated families, the sigma70 and the sigma54 families. The sigma70 family includes primary sigma factors (e.g., Bacillus subtilis sigma(A)) as well as related alternative sigma factors; sigma54 forms a distinct subfamily of sigma factors referred to as sigma(N) in almost all species for which these proteins have been characterized to date. We present several examples of alternative sigma factors that have been shown to contribute to virulence in at least one organism. For each sigma factor, when applicable, examples are drawn from multiple species.

FIG. 1.

(A) sigB operon structures in various gram-positive bacteria. Promoter sites are marked by arrows. P_A promoters are transcribed with RNAP-σ^A, and P_B promoters are transcribed with RNAP-σ^B. (B) Posttranslational regulation of σ^B activity via a partner-switching mechanism. Proteins shown are encoded by the B. subtilis and L. monocytogenes sigB operons depicted in panel A. Arrows indicate activation of protein activity, and T-bars indicate repression of protein activity. “P” represents a phosphate group. The proteins indicated by dark gray are encoded in all bacteria listed in panel A, whereas RsbU (light gray) is absent in the pathogenic Bacillus spp. and the proteins indicated by white are encoded only in L. monocytogenes and B. subtilis.

FIG. 2.

Examples of regulatory networks involving sigma factors and other transcriptional regulators or multiple sigma factors. (A) The σ^B-PrfA network of L. monocytogenes. Some genes are activated solely by σ^B (e.g., hfq and opuCA), some solely by PrfA (e.g., actA and hly), and some by both factors (e.g., inlA and bsh). (B) The short sigma factor cascade regulating type III secretion in P. syringae. σ^N mediates transcription of hrpL, which encodes a sigma factor responsible for transcription of the hrp and avr genes of the type II secretion system, as well as other virulence genes. All transcription depicted in panels A and B is the result of direct activity by the sigma factor or regulator at the promoter sites. (C) The complex interaction of several sigma factors that affect virulence in M. tuberculosis. Multiple sigma factors activate expression of other sigma factors and of virulence-associated genes (white). The interactions depicted here were deduced from global expression profiles and may be the result of either direct or indirect regulation by the sigma factor(s).