A Small Protein but with Diverse Roles: A Review of EsxA in Mycobacterium–Host Interaction

Abstract

As a major effector of the ESX-1 secretion system, EsxA is essential for the virulence of pathogenic mycobacteria, such as Mycobacterium tuberculosis (Mtb) and Mycobacterium marinum (Mm). EsxA possesses an acidic pH-dependent membrane permeabilizing activity and plays an essential role by mediating mycobacterial escape from the phagosome and translocation to the cytosol for intracellular replication. Moreover, EsxA regulates host immune responses as a potent T-cell antigen and a strong immunoregulator. EsxA interacts with multiple cellular proteins and stimulates several signal pathways, such as necrosis, apoptosis, autophagy, and antigen presentation. Interestingly, there is a co-dependency in the expression and secretion of EsxA and other mycobacterial factors, which greatly increases the complexity of dissecting the precise roles of EsxA and other factors in mycobacterium–host interaction. In this review, we summarize the current understandings of the roles and functions of EsxA in mycobacterial infection and discuss the challenges and future directions.

The C terminus of the mycobacterium ESX-1 secretion system substrate ESAT-6 is required for phagosomal membrane damage and virulence

“…The ESAT-6 M93T Mutant Retains Wild-Type Levels of Acidified Liposome Lysis Activity. Under acidic conditions (≤pH 5), ESAT-6 undergoes a conformational shift and inserts into liposomal membranes, resulting in their lysis (16,46). Based on these observations, ESAT-6's lysis of acidified liposomes has been used as a proxy for its role in phagosomal damage and permeabilization (16,23).…”

“…Under acidic conditions (≤pH 5), ESAT-6 undergoes a conformational shift and inserts into liposomal membranes, resulting in their lysis (16,46). Based on these observations, ESAT-6's lysis of acidified liposomes has been used as a proxy for its role in phagosomal damage and permeabilization (16,23). However, the relevance of the liposome lysis assay for ESAT-6's role in phagosomal damage has been unclear.…”

“…ESX-1's membranolytic activity had been ascribed to its major secreted substrate ESAT-6 (6 kDa early secretory antigenic target) (16). ESAT-6 was discovered as a secreted, immunodominant Mtb antigen long before the esx-1 locus was identified (17).…”

mTOR-regulated Mitochondrial Metabolism Limits Mycobacterium-induced Cytotoxicity

“…Studies in cultured cells have attributed this death to apoptosis, pyroptosis or necrosis (Augenstreich et al ., 2017; Beckwith et al ., 2020; Behar et al, 2010; Srinivasan et al, 2014) and the one in vivo study, also in zebrafish larvae, finds that ESX-1 induces apoptosis of granuloma macrophages (Davis and Ramakrishnan, 2009). For all these forms of death, phagosomal damage is widely considered to be a pre-requisite step, which is now confirmed to be mediated by ESAT-6 (Bao et al ., 2021; Osman et al ., 2022; Simeone et al ., 2021; Srinivasan et al ., 2014; Zhang et al ., 2016). We show here that ESAT-6’s ability to induce phagosomal damage is irrespective of whether the macrophage is mTOR-sufficient or -deficient, a finding that is important for its role in disease pathogenesis in normal hosts.…”

Host MKRN1-Mediated Mycobacterial PPE Protein Ubiquitination Suppresses Innate Immune Response

“…Mtb RDs encode about 11 PE/PPE proteins related with pathogenesis of Mtb , which are characterized by the highly conserved proline-glutamate (PE) or proline-proline-glutamate (PPE) motifs at the N terminus ( 7 ). Only a few RD-encoded proteins (e.g., RD1: ESAT-6 (Rv3874) and CFP-10 (Rv3875); RD2: MPT64 (Rv1980c); RD3: EST12 (Rv1579) and RD4: Rv0222) have been characterized and analyzed thus far ( 8 – 11 ). ESAT-6 and CFP-10 contain multiple T cell and B cell epitopes and are widely used in TB diagnosis and vaccine research ( 12 ).…”