SecA2 functions in the secretion of superoxide dismutase A and in the virulence of Mycobacterium tuberculosis

Abstract

Tuberculosis remains a severe worldwide health threat. A thorough understanding of Mycobacterium tuberculosis pathogenesis will facilitate the development of new treatments for tuberculosis. Numerous bacterial pathogens possess specialized protein secretion systems that are dedicated to the export of virulence factors. Mycobacterium tuberculosis is part of a developing group of pathogenic bacteria that share the uncommon property of possessing two secA genes (secA1 and secA2). In mycobacteria, SecA1 is the essential 'housekeeping' SecA protein whereas SecA2 is an accessory secretion factor. Here we demonstrate that SecA2 contributes to the pathogenesis of M. tuberculosis. A deletion of the secA2 gene in M. tuberculosis attenuates the virulence of the organism in mice. By comparing the profile of proteins secreted by wild-type M. tuberculosis and the DeltasecA2 mutant, we identified superoxide dismutase A (SodA) as a protein dependent on SecA2 for secretion. SodA lacks a classical signal sequence for protein export. Our data suggests that SecA2-dependent export is a new type of secretion pathway that is part of a virulence mechanism of M. tuberculosis to elude the oxidative attack of macrophages.

Extracellular Mycobacterial DNA-binding Protein 1 Participates in Mycobacterium-Lung Epithelial Cell Interaction through Hyaluronic Acid

“…1) imply that some machinery is present that transports MDP1 outside the cell membrane rather than retention on the cell surface due to cell lysis of bacteria. Certain proteins that lack signal sequence and a transmembrane domain, such as ESAT-6 (37), CFP-10 (38), HSP65 and superoxide dismutase (SOD) (39,40), and glutamine synthetase (39), are actively exported from mycobacteria and play significant roles in the pathogenesis. Further study is needed to clarify the issue of transportation of MDP1.…”

Mutually dependent secretion of proteins required for mycobacterial virulence

“…Of these, 53 were present in at least two of three samples. Seventy-five percent of the reproducibly identified proteins have predicted signal sequences, are ESX proteins (8), or have been shown to be secreted in a secA2-dependent fashion (21), indicating that our sampling enriched for secreted proteins. More proteins were identified in the H37Rv⌬RD1 culture filtrates (178 proteins were identified in three independently obtained samples).…”

β-Lactamase can function as a reporter of bacterial protein export during Mycobacterium tuberculosis infection of host cells

“…Sec substrates are translocated across the cytoplasmic membrane in an unfolded state, whereas Tat substrates are translocated in a folded conformation. M. tuberculosis also has at least two specialized protein export pathways: the SecA2-dependent system and the ESX-1 (ESAT-6) system (Braunstein et al, 2003;Guinn et al, 2004;Hsu et al, 2003;Pym et al, 2003;Stanley et al, 2003). Interestingly, both pathways appear capable of secreting specific subsets of proteins that lack conventional Sec or Tat signal sequences.…”