LppX is a lipoprotein required for the translocation of phthiocerol dimycocerosates to the surface of Mycobacterium tuberculosis

Abstract

Cell envelope lipids play an important role in the pathogenicity of mycobacteria, but the mechanisms by which they are transported to the outer membrane of these prokaryotes are largely unknown. Here, we provide evidence that LppX is a lipoprotein required for the translocation of complex lipids, the phthiocerol dimycocerosates (DIM), to the outer membrane of Mycobacterium tuberculosis. Abolition of DIM transport following disruption of the lppX gene is accompanied by an important attenuation of the virulence of the tubercle bacillus. The crystal structure of LppX unveils an U-shaped b-half-barrel dominated by a large hydrophobic cavity suitable to accommodate a single DIM molecule. LppX shares a similar fold with the periplasmic molecular chaperone LolA and the outer membrane lipoprotein LolB, which are involved in the localization of lipoproteins to the outer membrane of Gram-negative bacteria. Based on the structure and although an indirect participation of LppX in DIM transport cannot yet be ruled out, we propose LppX to be the first characterized member of a family of structurally related lipoproteins that carry lipophilic molecules across the mycobacterial cell envelope.

LspA inactivation in Mycobacterium tuberculosis results in attenuation without affecting phagosome maturation arrest

“…The physiology of M. tuberculosis is intimately linked to integrity of the cell wall, and some lipoproteins are involved in cell wall metabolism (LppX, LpqK, LppW; Sutcliffe & Harrington, 2004). LppX is required for the translocation of phthiocerol dimycocerosates to the outer membrane of M. tuberculosis, and disruption of lppX is accompanied by attenuation of the tubercle bacillus (Sulzenbacher et al, 2006). At a gross level, i.e.…”

The pleiotropic transcriptional response of Mycobacterium tuberculosis to vitamin C is robust and overlaps with the bacterial response to multiple intracellular stresses

“…Of these, lprK (of the mce1 operon) is believed to be involved in cell invasion and is repressed by RNI (Arruda et al, 1993;Ohno et al, 2003). The lppX gene may be involved in the transport of phthiocerol dimycocerosates to the bacterial outer membrane and its disruption leads to attenuation of virulence of Mtb (Sulzenbacher et al, 2006). The lppA gene product has been implicated in hostpathogen interactions as it is found only in pathogenic mycobacteria (Graña et al, 2010).…”

Lipidomics of host–pathogen interactions

“…The natures of major components are known. However, elucidation of the precise chemical composition of many lipid species and more importantly their biosynthetic pathways, transport [19] and dynamics leaves enormous room for further investigations. Such more detailed knowledge will enhance the drug development process which classically has been targeting cell wall biosynthesis.…”