Chapter 24 : Regulation of Envelope Stress Responses by

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This chapter discusses some of the stressors likely to target the cell envelope of during infection, and the corresponding regulatory elements expressed by the bacterium to counteract this stress. Phylogenetically, is a member of the phylum Actinobacteria, which also includes several notable human pathogens, including species of the genera , , , and . is a facultative intracellular pathogen, and its host range is restricted to humans. The bacterium is not normally found free within the environment, so its continued survival within the human population requires that it be transmitted directly from an infected individual with active disease to one that is susceptible to infection. Posttranslational phosphorylation of proteins was traditionally thought to be limited to eukaryotic cells. However, the discovery of two-component signal transduction systems (TCSSs) in bacteria shifted this paradigm to include phosphorylation of prokaryotic SKs on a conserved histidine residue and phosphorelay to a conserved aspartic acid residue on the cognate RRs. There is mounting evidence that PknB, and perhaps other STPKs, may also play an important regulatory role in the response of to environmental stress by directly regulating the activity of anti-sigma factors. A large body of work has helped to shape the current model of how senses cell envelope damage, including the regulatory mechanisms by which the bacterium responds to these stimuli.

Citation: Bretl D, Zahrt T. 2013. Regulation of Envelope Stress Responses by , p 465-489. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch24
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Figure 1

(A) The mycobacterial cell envelope is composed of four main compartments. The first is a typical bacterial plasma membrane (PM). Exterior to the PM is the cell wall, composed of several biomolecular moieties, including PG, AG, and mycolic acids (MA). Noncovalently attached to MA and other lipids of the cell wall layer is the OM. Finally, the entire cell is surrounded by a loosely associated capsule-like structure (CAP) composed primarily of proteins and carbohydrates. Lipids making up the MA layer are depicted as different lengths and colors to illustrate the variety of long-chain fatty acids found in the mycobacterial cell envelope. The image is not to scale. (B) Cryo-electron micrograph of the cell envelope. The PM and OM are visible and enclose an area of different electron density that is presumed to contain PG, AG, and MA. This image is modified from that taken by Hoffmann et al. ( ) and is used with permission from the National Academy of Sciences. doi:10.1128/9781555818524.ch24f1

Citation: Bretl D, Zahrt T. 2013. Regulation of Envelope Stress Responses by , p 465-489. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch24
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Figure 2

is exposed to a variety of environmental stressors found both outside and inside the host. M. tuberculosis is exposed to alterations in temperature, UV radiation, and desiccation during transmission from an infected individual to a susceptible host. Following inhalation and deposition in lung tissues, the bacterium encounters host alveolar surfactant proteins and cationic peptides which may perturb the bacterial cell envelope. Macrophages that ingest the tubercle bacillus generate bactericidal products, including ROI and RNI. Finally, M. tuberculosis establishes persistent infection within granulomatous structures generated following an adaptive host immune response. Within this environment, the bacterium must adapt to a variety of potentially adverse conditions, including altered nutrients, elevated levels of NO, toxic fatty acids, and low oxygen concentrations. doi:10.1128/9781555818524.ch24f2

Citation: Bretl D, Zahrt T. 2013. Regulation of Envelope Stress Responses by , p 465-489. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch24
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Figure 3

Cell envelope stress response network of . Cell envelope stress that generates PG fragments is sensed by PknB via its PASTA domains. Activation of PknB results in phosphorylation of other STPKs, including PknA and several determinants involved in PG synthesis, cell division, and mycolic acid production. Additionally, PknB and other STPKs phosphorylate EmbR, leading to increased expression of the embCAB operon and increased AG synthesis. PknB phosphorylation of the SigE anti-sigma factor, RseA, results in RseA degradation by the ClpC1P2 protease complex. Dissociated SigE directs upregulation of several genes, including , , 2, and . Cell envelope damage is also sensed by the extracytoplasmic domain of MprB. Activation of MprB leads to phosphorelay to MprA, and phosphorylated MprA directs transcription of , , and several other genes. Finally, ClgR directs expression of the genes encoding the ClpC1P2 protease, as well as Ppk1, which is responsible for generation of polyphosphate molecules that can be utilized by MprB to alternatively phosphorylate MprA. doi:10.1128/9781555818524.ch24f3

Citation: Bretl D, Zahrt T. 2013. Regulation of Envelope Stress Responses by , p 465-489. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch24
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Figure 4

PknA and PknB phosphorylate several proteins involved in biosynthesis or maintenance of the cell envelope. PknA phosphorylates MurD and FtsZ, while PknB phosphorylates PbpA, Rv0020c, and PapA5. Both kinases have been shown to phosphorylate Wag31, GlmU, and FipA. PknA and PknB also phosphorylate all of the enzymes of the core mycolic acid synthesis machinery. Phosphorylation of these enzymes is generally inhibitory, with the exception of KasB (stimulatory) and Pks13 (unknown). It is important to note that the substrates shown in this figure are not an exhaustive list, and other substrates having functions not directly related to cell envelope maintenance exist. Furthermore, other STPKs not shown are able to phosphorylate several of these substrates. Finally, the phosphorylation of the kinase substrates and the kinases themselves is reversible via dephosphorylation by PstP, the serine-threonine phosphatase (not shown). doi:10.1128/9781555818524.ch24f4

Citation: Bretl D, Zahrt T. 2013. Regulation of Envelope Stress Responses by , p 465-489. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch24
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Table 1

Regulators of cell envelope and environmental stresses known to activate their signaling

Citation: Bretl D, Zahrt T. 2013. Regulation of Envelope Stress Responses by , p 465-489. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch24
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Table 2

Genes coregulated by transcriptional regulators associated with cell envelope stress

Citation: Bretl D, Zahrt T. 2013. Regulation of Envelope Stress Responses by , p 465-489. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch24

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