Model of Type VII Secretion System Figure 2. Proposed model for secretion of substrates (CFP-10, ESAT-6, EspA, EspC, EspB) using Type VII secretion system. The various steps involved are indicated by numbers and are described below: (1) Initial activation by WhiB6; (2) Transcriptional regulation of the secretory proteins by Rv3866 and PhoP; (3) Multimeric assembly of secretory proteins by Rv3868; (4) Pairing up of secretory protein EspB with Rv3879c; (5a) Recruitment of CFP-10/ESAT-6/EspA/EspC multimer by Rv3870 and Rv3871 to the inner membrane pore (Rv3877); (5b) Recruitment of EspB/Rv3879c pair by Rv3870 and Rv3871 to the inner membrane pore (Rv3877); (6) Interaction of MycP1 with Rv3877; (7) Inner membrane translocation of secretory proteins; (8) Cleavage of EspB by MycP1; (9) Mycomembrane translocation of secretory proteins. The dashed arrows show interaction between the components connected by the arrow. doi:10.1371/journal.pone.0027980.g002 involves the same machinery used by the other secretory proteins (CFP-10/ESAT-6 and EspA/EspC). Regulation of protein secretion The cleavage of EspB by MycP1 leads to a controlled secretion of both the CFP-10/ESAT-6/EspA/EspC multimer and EspB. The controlled secretion of these proteins is probably achieved due to their competition for translocation (through the mycomembrane) using the same machinery. However, the increase in secretion of CFP-10/ ESAT-6 despite the absence of the protease activity of MycP1 as observed by Ohol et al. (2010) is interesting and the molecular mechanism governing this phenomena needs to be resolved experimentally in the laboratory. On the other hand, in the absence of MycP1, neither the cleavage of ubiquitin-like domain of Rv3877 nor its interaction with MycP1 occurs. Thus, the gate remains closed resulting in the loss of secretion of all secretory proteins. Conclusion The present study, for the first time, suggests probable functional roles for some of the previously uncharacterized components of ESX-1 secretion system, namely Rv3866, Rv3876, Rv3869 and Rv3882c. While Rv3866 has been proposed to be involved in the transcriptional activation of the secretion machinery, Rv3876 has been predicted to be a negative regulator of this machinery. On the other hand, Rv3869 and Rv3882c have been identified as probable components of the mycomembrane translocation apparatus. The present analysis also proposes a few components that were not known to be associated with the ESX-1 secretion system. These include an additional transcriptional regulator (WhiB6) and components associated with transport through the mycomembrane (MCE Cluster 1 proteins). With regards to the secretory proteins of the ESX-1 secretion pathway, the current analysis indicates that the secretory protein PLoS ONE | www.plosone.org 8 November 2011 | Volume 6 | Issue 11 | e27980