The ins and outs of Mycobacterium tuberculosis protein export

Abstract

Mycobacterium tuberculosis is an important pathogen that infects approximately one third of the world’s population and kills almost two million people annually. An important aspect of M. tuberculosis physiology and pathogenesis is its ability to export proteins into and across the thick mycobacterial cell envelope, where they are ideally positioned to interact with the host. In addition to the specific proteins that are exported by M. tuberculosis, the systems through which these proteins are exported represent potential targets for future drug development. M. tuberculosis possesses two well-known and conserved export systems: the housekeeping Sec pathway and the Tat pathway. In addition, M. tuberculosis possesses specialized export systems including the accessory SecA2 pathway and five ESX pathways. Here we review the current understanding of each of these export systems, with a focus on M. tuberculosis, and discuss the contribution of each system to disease and physiology.

Interaction of Mycobacterium tuberculosis with Host Cell Death Pathways

“…SodA is secreted via the SecA2 secretion system in Mtb, and a secA2 deletion mutant was attenuated in mice (Braunstein et al 2003) and has a proapoptosis phenotype because of its defect in SodA secretion (Hinchey et al 2007). However, the SecA2 system also affects other responses of the host cell and consequently these pleiotropic effects of the mutant make the interpretation of the cause of the in vivo attenuation difficult (Ligon et al 2012). For example, the early growth defect of the secA2 mutant is not caused by a lack in SodA export, because expressing a SodA protein secreted via the SecA1 pathway could not reverse the phenotype (Sullivan et al 2012).…”

A Multicopper Oxidase Is Required for Copper Resistance in Mycobacterium tuberculosis

“…MymT protects the cytoplasm against copper stress by sequestering four to six copper ions (54). TatB recognizes and binds the twinarginine (RR) motif on the N terminus of MmcO prior to translocation (73). MmcO is translocated to the periplasm by the twin-arginine translocation system (TatABC), probably as a folded protein (42).…”

Label-free Quantitative Proteomics Reveals a Role for the Mycobacterium tuberculosis SecA2 Pathway in Exporting Solute Binding Proteins and Mce Transporters to the Cell Wall*

“…M. tuberculosis proteins that are exported from the cytoplasm to the bacterial cell wall or into the host environment are ideally positioned for host-pathogen interactions or physiologic processes important to infection, such as nutrient uptake and cell wall biogenesis (3). M. tuberculosis has several systems for exporting proteins to extracytoplasmic locations, one of which is the SecA2-dependent protein export pathway (4). In M. tuberculosis, SecA2 is required for virulence in both mice and macrophage models of infection, making the identification of SecA2-dependent exported proteins important for understanding M. tuberculosis pathogenesis (5-7).…”