The Enigmatic Esx Proteins: Looking Beyond Mycobacteria

Unnikrishnan, Meera; Constantinidou, Chrystala; Palmer, Tracy; Pallen, Mark J.

doi:10.1016/j.tim.2016.11.004

Cited by 93 publications

(79 citation statements)

References 94 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our findings are consistent with reports of PE/PPE family proteins impacting the secretion of specific proteins in pathogenic mycobacteria. For example, mutations in the PPE38 protein have been shown to hinder the secretion of PE_PGRS proteins in M. tuberculosis (84). Likewise, the ESX-5a accessory region includes PE/PPE substrate pairs that are required for the secretion of a subset of ESX-5 substrates (85,86).…”

Section: Discussionmentioning

confidence: 99%

A New ESX-1 Substrate in Mycobacterium marinum That Is Required for Hemolysis but Not Host Cell Lysis

et al. 2019

View full text Add to dashboard Cite

The ESX-1 (ESAT-6 system 1) secretion system plays a conserved role in the virulence of diverse mycobacterial pathogens, including the human pathogen Mycobacterium tuberculosis and M. marinum, an environmental mycobacterial species. The ESX-1 system promotes the secretion of protein virulence factors to the extracytoplasmic environment. The secretion of these proteins triggers the host response by lysing the phagosome during macrophage infection. Using proteomic analyses of the M. marinum secretome in the presence and absence of a functional ESX-1 system, we and others have hypothesized that MMAR_2894, a PE family protein, is a potential ESX-1 substrate in M. marinum. We used genetic and quantitative proteomic approaches to determine if MMAR_2894 is secreted by the ESX-1 system, and we defined the requirement of MMAR_2894 for ESX-1-mediated secretion and virulence. We show that MMAR_2894 is secreted by the ESX-1 system in M. marinum and is itself required for the optimal secretion of the known ESX-1 substrates in M. marinum. Moreover, we found that MMAR_2894 was differentially required for hemolysis and cytolysis of macrophages, two lytic activities ascribed to the M. marinum ESX-1 system. IMPORTANCE Both Mycobacterium tuberculosis, the cause of human tuberculosis (TB), and Mycobacterium marinum, a pathogen of ectotherms, use the ESX-1 secretion system to cause disease. There are many established similarities between the ESX-1 systems in M. tuberculosis and in M. marinum. Yet the two bacteria infect different hosts, hinting at species-specific functions of the ESX-1 system. Our findings demonstrate that MMAR_2894 is a PE protein secreted by the ESX-1 system of M. marinum. We show that MMAR_2894 is required for the optimal secretion of mycobacterial proteins required for disease. Because the MMAR_2894 gene is not conserved in M. tuberculosis, our findings demonstrate that MMAR_2894 may contribute to a species-specific function of the ESX-1 system in M. marinum, providing new insight into how the M. marinum and M. tuberculosis systems differ.

show abstract

Section: Discussionmentioning

confidence: 99%

A New ESX-1 Substrate in Mycobacterium marinum That Is Required for Hemolysis but Not Host Cell Lysis

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Type VII secretion systems are responsible for secreting virulence factors and other effectors (Unnikrishnan et al 2017). EccC proteins, which typically contain three ATPase domains, have been demonstrated to be required for secretion of substrates by maintaining a stable membrane complex and by acting as a motor to translocate substrates across membrane (Stanley et al 2003;Houben et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Structural insights into substrate recognition by the type VII secretion system

et al. 2019

View full text Add to dashboard Cite

Type VII secretion systems (T7SSs) are found in many disease related bacteria including Mycobacterium tuberculosis (Mtb). ESX-1 [early secreted antigen 6 kilodaltons (ESAT-6) system 1] is one of the five subtypes (ESX-1∼5) of T7SSs in Mtb, where it delivers virulence factors into host macrophages during infection. However, little is known about the molecular details as to how this occurs. Here, we provide high-resolution crystal structures of the C-terminal ATPase 3 domains of EccC subunits from four different Mtb T7SS subtypes. These structures adopt a classic RecA-like ɑ/β fold with a conserved Mg-ATP binding site. The structure of EccCb1 in complex with the C-terminal peptide of EsxB identifies the location of substrate recognition site and shows how the specific signaling module "LxxxMxF" for Mtb ESX-1 binds to this site resulting in a translation of the bulge loop. A comparison of all the ATPase 3 structures shows there are significant differences in the shape and composition of the signal recognition pockets across the family, suggesting that distinct signaling sequences of substrates are required to be specifically recognized by different T7SSs. A hexameric model of the EccC-ATPase 3 is proposed and shows the recognition pocket is located near the central substrate translocation channel. The diameter of the channel is ∼25-Å, with a size that would allow helix-bundle shaped substrate proteins to bind and pass through. Thus, our work provides new molecular insights into substrate recognition for Mtb T7SS subtypes and also a possible transportation mechanism for substrate and/or virulence factor secretion.

show abstract

“…Accordingly, the mel2 operon is implicated in mycobacterial resistance to both reactive oxygen and nitrogen species (27). Another bioinformatically predicted RNA from M tuberculosis that we validated experimentally, resides upstream of espE (ESX-1 secretion associated protein E), the first gene of the ESX-1 operon in M. tuberculosis (28). This RNA is conserved among the strains of the MTB complex ( Figure 5B).…”

Section: Antar-target Rnas Typically Reside Upstream Of Lipid Metabolmentioning

confidence: 95%

Non-coding RNAs control metabolic state in mycobacteria

Mehta

Anjali

Achuthan

et al. 2019

Preprint

View full text Add to dashboard Cite

Non-coding RNAs play pivotal roles in bacterial signaling. However, RNAs from certain phyla (specially high-GC actinobacteria) remain elusive. Here, by revamping existing approaches we discover a family of structurally conserved RNAs in actinobacteria. These RNAs function by the recruiting ANTAR proteins to select transcripts; regulating them via translational repression. By overlapping with ORF start sites, these RNAs provide mechanisms by which even leader-less transcripts are regulated. In mycobacteria, transcripts marked by ANTAR-target RNAs are few but encode important redox enzymes especially involved in lipid metabolism. Notably, the cellular response to ANTAR-regulation is hierarchical, wherein immediate metabolic changes induced by ANTAR-RNA binding are amplified through a global transcriptomic response. This includes several genes from oxidative/reductive pathways; ultimately switching cells towards reductive metabolism. This discovery of ANTAR-target RNAs and associated regulation places RNAs as crucial players in controlling metabolic flexibility of mycobacteria, proposing a prominent role for ANTAR regulation across actinobacteria.

show abstract

The Enigmatic Esx Proteins: Looking Beyond Mycobacteria

Cited by 93 publications

References 94 publications

A New ESX-1 Substrate in Mycobacterium marinum That Is Required for Hemolysis but Not Host Cell Lysis

A New ESX-1 Substrate in Mycobacterium marinum That Is Required for Hemolysis but Not Host Cell Lysis

Structural insights into substrate recognition by the type VII secretion system

Non-coding RNAs control metabolic state in mycobacteria

Contact Info

Product

Resources

About