The RD1 (ESX-1) protein secretion complex (Type VII protein secretion system, T7SS). EccA1 may be a secreted protein while ECCB1 - E1 may comprise the system (Houben et al. 2012). This system (ESX-1) is present in the avirulent species, Mycobacterium smegmatis, where it is involved in conjugation (Coros et al. 2008). ESX-1 uses the ESX-1-specific chaparone protein, EspG to interact with the secreted PE/PPE complex, while a homologous EspG specific for ESX-5 functions with the PE/PPE complex secreted by ESX-5. Thus, EspG proteins may be system-specific chaparones for T7SSs (Daleke et al. 2012). The main secreted virulence protein complex is a heterodimer: EsxA(ESAT-6)/EsxB(CFP-10) (Rosenberger et al. 2012). EccB, a periplasmic homoheximer with the ATP-binding active site shared by two adjacent subunits, may act as the energy provider in the transport of T7SS virulence factors and may be involved in the formation of a channel across the mycomembrane (Zhang et al. 2015). ESX-1 functions in resistance to and evasion of host responses. It induces phagosomal rupture which releases bacteria into the cytosol of the host phagocytes (Gröschel et al. 2016). ESX-1 secrete EsxA and EsxB, which form a heterodimer, seem to have differing functions as EsxA can disrupt lipid bilayers (RBC and artificial membranes. Thus EsxA may form pores as a prelude to membrane disruption (Gröschel et al. 2016).
The RD1 complex (Rv3868, Rv3870-3877 and Rv3615c and Rv3614c) of Mycobacterium tuberculosis
Rv3868 (EccA1) (O69733)
Rv3869 (EccB1) (O69734)
Rv3870 (EccCa1) (O69735)
Rv3871 (EccCb1) (O69736)
Rv3872 (EccC1a) (Q79F93)
Rv3873 (EccC1b) (Q79F92)
Rv3874 (Cfp-10) (P0A566)
Rv3875 (Esat-6) (P0A564)
Rv3876 (EspI) (O69740)
Rv3877 (EccD1) (O69741)
Rv1794 (EccE1) (O05462)
Rv3615c (Snm9) (P65087)
Rv3614c (Snm10) (O06269)
The Esx-2 type VII protein secretion system
Esx-2 protein secretion system of Mycobacterium tuberculosis
The Esx-3 type VII protein secretion system. Controlled by the iron-dependent regulator, IdeR and the Zn2+-uptake regulator, Zur. ESX-3 is involved in metal ion homeostasis, consistent with its essentiality for in vitro growth (Simeone et al. 2009). Exports the EsxG-EsxH complex which contains a Zn2+ binding site in EsxH and may function in Zn2+ acquisition (Ilghari et al. 2011). The system plays an essential role in siderophore-mediated iron uptake (Gröschel et al. 2016).
Esx-3 of Mycobacterium tuberculosis
The Type VII secretion system (T7SS or MPSS); the ESAT-6-like protein secretion system, ESX-5 (Abdallah et al., 2006; Sayes et al., 2012; Houben et al. 2012). Mediates the secretion of the EsxN, PPE [pro-pro-glu motif] and PE_PGRS proteins (Deng and Xie 2012). The EccB5, EccC5, EccD5 and EccE5 proteins form a membrane complex of about 1.5 MDa while EccA5 may be the channel-forming subunit that exports the substrate proteins (Bunduc et al. 2021). Thus, ESX-5 exports protein substrate (Houben et al. 2012). PE25/PPE41form a heterodimer that is targeted to the T7SS, ESX5, by a C-terminal signal in PE25 which is necessary but not sufficient for targeting to ESX5 (Daleke et al. 2012). An esx-5 mutant is strongly impaired in the uptake and utilization of hydrophobic carbon sources. Possibly the ESX-5 system is responsible for the transport of cell envelope proteins that are required for nutrient uptake (Ates et al. 2015). Mycobacterium tuberculosis releases membrane vesicles (MV) that modulate host immune responses and aid in iron acquisition, and the ESX-5 system seems to play a role, together with the SenX3-RegX3 complex which regulates the process (White et al. 2018). The 3-D structure of ESX-5 has been determined (Bunduc et al. 2021) (see ESX5 family description, paragraph 11 for details). The structure of the mycobacterial ESX-5 type VII secretion system pore complex has been determined (Beckham et al. 2021). The high-resolution structure of the 2.1-megadalton ESX-5 core complex captured a dynamic, secretion-competent conformation of the pore within a well-defined transmembrane section, sandwiched between two flexible protein layers at the cytosolic entrance and the periplasmic exit. Beckham et al. 2021 proposed that this flexibility endows the ESX-5 machinery with large conformational plasticity required to accommodate targeted protein secretion. A highly dynamic state of the pore may represent a fundamental principle of bacterial secretion machineries.
The potential 8 protein ESX5 system of Mycobacterium tuberculosis
Rv1782 (EccB5) (506 aas) (O53933)
Rv1783 (EccC5a) (435 aas; resembles Rv3870 under TC# 9.A.25.1.1) (O53934)
Rv1784 (EccC5b) (932 aas; resembles Rv3871 and regions of Rv3870 under TC# 9.A.25.1 as well as Spo and FtsK under TC# 3.A.12) (O53935)
Rv1794 (300aas) (O53943)
Rv1795 (EccD5) (503 aas; resembles Rv3877 under TC# 9.A.25) (O53944)
MycP5 (585 aas; resembles proteins of the AT family under TC# 1.B.12: TC# 1.B.12.5.1 and 1.B.12.9.1) (O53945)
Rv1797 (EccE5) (199aas) (O53946)
Rv1798 (EccA5) (610 aas; resembles ATPases) (P63744)
Esx-4 secretion system. Gray et al. 2016 showed that ESX-4 is essential for conjugal recipient activity in Mycobacterium smegmatis. Transcription of esx4 genes in the recipient requires coculture with a donor strain and a functional ESX-1 apparatus in the recipient. Conversely, mutation of the donor ESX-1 apparatus amplifies the esx4 transcriptional response in the recipient. The effect of ESX-1 on esx4 transcription correlates with conjugal DNA transfer efficiencies. Thus, intercellular communication via ESX-1 controls the expression of its evolutionary progenitor, ESX-4, to promote conjugation between mycobacteria. The eight proteins listed under this TC# are all encoded withing a single gene cluster (Gray et al. 2016).
Esx-4 of Mycobacterium smegmatis
Msmeg_1537 of 368 aas (A0QSN1)
EccB4 of 458 aas; Membrane protein with 1 N-terminal TMS (A0QSM7)
EccD4 of 437 aas; Membrane protein with 11 predicted TMSs (A0QSM9)
MycP4 of 442 aas with 2 TMSs (N- and C-terminal) as well as 7 central moderately hydrophobic peaks that could be, but were not predicted to be TMSs. Predicted to have serine endopeptidase activity. (A0QSM8)
EccA4 of 574 aas; an AAA ATPase (A0QNI9)
EccC4 of 1211 aas; FtsK/SpoIIIE ATPase (A0QSN0)
EsxU of 103 aas; ESAT-6-like protein (L8FHH3). May be a secreted pore-forming protein (see TC# 1.C.95.
EsxT of 98 aas; ESAT-6-like protein (L8FGI7). May be a secreted pore-forming protein (see TC# 1.C.95.