# Bacterial Flagellar Filament: A Supramolecular Multifunctional Nanostructure
## 5 Protein Synthesis, Export and Filament Elongation
### Genetic Regulation of FliC and FliD
In some Gram-positive bacteria, changes in the environmental conditions such as nutrient limitation induce variations in the levels of the intracellular messengers guanosine tetra/pentaphosphate, (p)ppGpp, guanosine nucleoside triphosphate (GTP) and branched chain amino-acid pools. These variations are detected by a conserved GTP-sensing protein CodY and a global regulator CsrA that modulate flagellin expression. Cell motility can be repressed under elevated intracellular cyclic-di-GMP levels, by impeding transcription of some of the flagellum genes [112; 113; 114; 115; 116]. Indeed, the expression of _fliD_ and _fliC_ is repressed in phosphodiesterase 3 (PDE3) knockout mutants triggered by elevated c-di-GMP accumulation [117]. Because the presence of flagellin can be deleterious to the bacterium on account of inducing host immunity, flagellated bacteria downregulate (or turn off) flagellin expression during the host invasion to avoid host immune responses. Therefore, normal microbiota within the healthy adult mammalian gut has been shown to have overall relatively low levels of flagellin expression, while TLR5\(-/-\) mice exhibited a diversity of gut microbiome members with overexpressed flagellar genes [118; 119]. Both commensal gut strains of motile _E. coli_ and pathogenic _S. Typhimurium strains strongly down-regulate their genes coding for flagellar machinery and lose their motility once inside the host [120; 121]. Under environmental temperature conditions (22-30 \({}^{\circ}\)C), the expression of flagellar genes in the human pathogens _Listeria monocytogenes_ and _Legionela pneumophila_ is normal, but significantly reduced when raised to 37 \({}^{\circ}\)C, revealing temperature-dependent transcription mainly controlled by the protein GmaR, which acts as a protein expression thermostat [122; 123]. These types of system provide a pathogen with the ability to turn off immune-stimulating antigens before they trigger adverse host defense mechanisms once inside their target host. Regulation of flagellin expression also occurs on the post-transcriptional level by proteins that bind to the untranslated leader region of the flagellin mRNA, affecting transcript stability and/or ribosome access [124; 125; 126]. For instance, the RNA-binding protein CsrA of _B. burgdorferi_ specifically mediates synthesis of the major flagellin by inhibiting translation initiation of its transcript. In some cases, post-transcriptional regulators repress the accumulation of flagellin when cells are defective for flagellar hook assembly [127; 128]. An assembly checkpoint that prevents flagellin translation and assembly prior to hook completion was discovered in _B. subtilis_. This is governed by a homeostatic mechanism in which the flagellin protein itself is a critical regulator. In a partner switching mechanism, the flagellar assembly factor FliW binds flagellin, while a global regulator CsrA binds flagellin mRNA, repressing its translation. After completion of the hook, flagellin is secreted, and the released FliW binds CsrA, thus derepressing flagellin translation [129]. An interesting case is _A. missouriensis_, in which all flagellar genes are transcribed simultaneously during sporangium formation and there is no checkpoint mechanism in the process of flagellar gene transcription to optimize the efficiency of the flagellar assembly [103]. The post-transcriptional level of regulation between protein production and assembly could play an important role, although this remains unknown.