Esx-3 and mycobactin-mediated iron acquisition in mycobacteria

Mycobacteria use multiple systems to transport molecules across the thick, waxy cell wall. Unique among these are the non-classical Esx secretion systems. Whereas Esx-1 is essential for virulence of Mycobacterium tuberculosis , the causative agent of tuberculosis, Esx-3 is essential for in vitro growth. To compete for the limited iron available in the host and the environment, mycobacteria use mycobactins, a class of high-affinity iron-binding molecules called siderophores. In the absence of Esx-3, these organisms synthesize mycobactins but are unable to utilize the iron bound to them. Individual components of the Esx-3 system are also required for utilization of ferri-mycobactins. It appears that while Ms0607, an AAA ATPase, and Ms0614, a transmembrane protein, are core components of the Esx-3 machinery, Ms0615, a secreted protease, plays a supporting role in Esx-3 function. These results correspond well to those from the Esx-1 system, where Ms0607 and Ms0614 paralogs are required for Esx-1-mediated secretion and virulence while the Ms0615 paralog is often dispensible for function. Mycobacteria thus employ a specialized secretion system for acquiring iron from siderophores. Expression of esx -3 varies with the mycobactin biosynthesis genes under a variety of stress conditions. Mycobacteria that are unable to synthesize or utilize mycobactins are impaired for response to several of these conditions, including oxidative stress, biofilm formation and cell wall perturbation. These mutants have additional alterations in sliding motility and redox homeostasis. The phenotypes are largely independent of iron availability and support a model in which mycobactin and Esx-3 contribute to normal mycobacterial growth under iron-replete conditions. Why is Esx-3 essential in M. tuberculosis but not the model organism M. smegmatis ? M. smegmatis may use alternate iron transporters not present in M. tuberculosis to acquire this vital nutrient. Alternatively, mycobactins themselves may be essential in M. tuberculosis . It may be that the mycobactin pathway, including Esx-3-dependent utilization, functions similarly across mycobacterial species, but that the absolute requirement for that function varies according to lifestyle and niche.