Get the Message Out: Cyclic-Di-GMP Regulates Multiple Levels of Flagellum-Based Motility

Flagella are complex organelles whose synthesis depends upon approximately 50 gene products.Not surprisingly, multiple mechanisms control and direct flagellar biogenesis (reviewed in references 1, 15, and 55).Perhaps best understood is the control exerted at the level of transcription: hierarchies exist, such that the flagellar structural proteins are synthesized only under proper conditions and at the time each is needed for assembly.Many bacteria also possess posttranscriptional mechanisms that control translation or protein stability.Assembly itself also occurs in a highly ordered fashion, with the insertion of one component building on the insertion of a previous subunit.In the best-characterized bacteria, flagellar biogenesis begins with the insertion of an inner membrane protein called FliF (Fig. 1).Building on the assembled FliF subunits are proteins that comprise the flagellar type III secretory (TTS) apparatus.This device exports the protein subunits required to build the basal body, which includes both a cytoplasmic switching device and a complex of rod and ring proteins that spans the two membranes of the gram-negative bacterium.The completed basal body provides a narrow channel through which the more external components exit the cell for assembly.These external components include the hook (a flexible linker comprised of over 100 identical subunits) and the filament (a semirigid propeller built from thousands of flagellin subunits).Once assembled, the flagellum rotates, a process powered by the proton (or sodium) motive force via motor proteins localized in the cytoplasmic membrane in close proximity to the switching device.The direction of rotation is dictated by the switching device, which interfaces with a signaling pathway that delivers information about the cell's physicochemical environment.Chemotaxis, the resulting behavior, permits cells to migrate toward favorable environments.Finally, some bacteria eject their fully functional flagellum in coordination with the cell cycle.In recent years, researchers have discovered a new layer of regulation on top of the already sophisticated control of flagellar biogenesis and function.This layer depends on bis-(3Ј,5Ј)cyclic diguanylic acid (also known as cyclic diguanylate, or c-di-GMP), a novel second messenger that apparently is unique to bacteria.This newly appreciated second messenger