PE_PGRS3 ensures provision of the vital phospholipids cardiolipin and phosphatidylinositols by promoting the interaction betweenM. tuberculosisand host cells

Abstract

PE_PGRS proteins of Mycobacterium tuberculosis ( Mtb ) constitute a large family of complex modular proteins whose role is still unclear. Among those, we have previously shown, using the heterologous expression in Mycobacterium smegmatis , that PE_PGRS3 containing a unique arginine-rich C-terminal domain, promotes adhesion to host cells. In this study, we investigate the role of PE_PGRS3 and its C-terminal domain directly in Mtb using functional deletion mutants. The results obtained here show that PE_PGRS3 is localized on the mycobacterial cell wall and its arginine-rich C-terminal region protrudes from the mycobacterial membrane and mediates Mtb entry into epithelial cells. Most importantly, this positively charged helical domain specifically binds phosphorylated phosphatidylinositols and cardiolipin, whereas it is unable to bind other phospholipids. Interestingly, administration of cardiolipin and phosphatidylinositol but no other phospholipids was able to turn-off expression of pe_pgrs 3 activated by phosphate starvation conditions. These findings suggest that PE_PGRS3 has the key role to serve as a bridge between mycobacteria and host cells by interacting with specific host phospholipids and extracting them from host cells, for their direct integration or as a source of phosphate, during phases of TB pathogenesis when Mtb is short of phosphate supply.

PGRS domain structures: Doomed to sail the mycomembrane

“…The protease domain of PE_PGRS35 localizes in the unique C-terminal domain that is positioned to recognize and cleave off the tubular-like PE domain (Fig 1A). ExperimentalAU : Pleasecheckifthechangesmadeinthes data indicate that cleavage of PE_PGRS proteins remove approximately 11 kDa fragment, corresponding to approximately 110 N-terminal amino acids [13,14], though the exact cleavage site has not yet been identified. These observations, together with the predicted structure of the PE_PGRSs (see below), suggest that cleavage of the PE domain may occur upstream the PGRS domain.…”

Imidazole-Thiosemicarbazide Derivatives as Potent Anti-Mycobacterium tuberculosis Compounds with Antibiofilm Activity

“…Furthermore, the authors suggested the involvement of PE_PGRS3 in scavenging lipids, which might be utilized as a carbon source by intracellularly located Mtb . Additionally, De Maio et al documented that the PE_PGRS3 protein, once translocated through the plasma membrane through an ESX5-dependent mechanism [ 57 , 58 ], remains associated with the mycobacterial membrane or may possibly be released to exert its activity and serve as a bridge between pathogen and the target host cells [ 59 ].…”

Unraveling the potential of graphene quantum dots against Mycobacterium tuberculosis infection

“…Additionally, macrophages exposed to GQDs increase the presence of phosphoglycerides, sphingolipids, and oxidized lipids ( Shao et al, 2023 ). While not completely elucidated, the role of host lipids and the changes associated with Mtb infection, play a key role in the pathogenesis of TB ( De Maio et al, 2021 ). Indeed, we have recently demonstrated that phosphoglycerides such as phosphorylated phosphatidylinositol (PtdIns), cardiolipin (CL), and phosphatidic acid (PA), were recognized by a surface protein of Mtb which appears to ensure phosphate acquisition from the environment and mediate adhesion to host cell.…”