Lipoprotein synthesis in mycobacteria

Abstract

Lipoproteins are a functionally diverse class of secreted bacterial proteins characterized by an Nterminal lipid moiety. The lipid moiety serves to anchor these proteins to the cell surface. Lipoproteins are synthesized as pre-prolipoproteins and mature by post-translational modifications. The post-translational modifications are directed by the lipobox motif located within the signal peptide. Enzymes involved in lipoprotein synthesis are essential in Gram-negative bacteria but not in Gram-positve bacteria. Inactivation of genes involved in lipoprotein synthesis attenuates a variety of Gram-positive pathogens, including Mycobacterium tuberculosis. The attenuated phenotype of these mutants indicates an important role of lipoproteins and lipoprotein synthesis in bacterial virulence. M. tuberculosis, the causative agent of tuberculosis, is one of the most devastating pathogens in the world. This article reviews recent findings on the synthesis, localization and function of lipoproteins in mycobacteria. IntroductionLipoproteins are a functionally heterogeneous class of proteins universally present in bacteria; typically between 1 % and 3 % of bacterial genomes encode lipoproteins (Babu et al., 2006; http://www.mrc-lmb.cam.ac.uk/genomes/ dolop/). Lipoproteins represent a subgroup of secreted proteins characterized by the presence of a lipobox. The lipobox motif is located in the C-terminal part of the leader peptide and consists of four amino acids [LVI/ASTVI/GAS/ C] (Babu et al., 2006). This motif functions as a recognition signal for lipid modification, which is made on the conserved and essential cysteine residue. Precursor lipoproteins are mainly translocated in a Sec-dependent manner across the plasma membrane and are modified subsequently. Recent investigations indicate that lipoproteins may also be translocated by the twin-arginine translocation (Tat) system (McDonough et al., 2005). However, this pathway presumably is of minor importance because the number of lipoproteins translocated via the Tat transporter is rather small. Modification of precursor proteins is mediated by the consecutive activity of three enzymes: phosphatidylglycerol-pre-prolipoprotein diacylglyceryl transferase (Lgt), prolipoprotein signal peptidase/signal peptidase II (LspA) and phospholipid-apolipoprotein Nacyltransferase (Lnt) (Fig. 1). While Lgt and LspA are universally present in bacteria, Lnt has been reported to be restricted to Gram-negatives (Wu, 1996). The lipid residue covalently linked to the conserved cysteine moiety is thought to allow for anchoring of proteins in biological membranes by means of hydrophobic interaction. In Grampositive bacteria, cell-associated lipoproteins are found in the plasma membrane. In Gram-negative bacteria the majority of cell-associated lipoproteins are found in the outer membrane -only about 10 % stay anchored in the plasma membrane. Lipoproteins may be divided into five general groups according to their function in adhesion and invasion, cell wall synthesis, nutrient uptake, degradative process...

Mycobacterial Lipopeptides Elicit CD4+ CTLs in Mycobacterium tuberculosis-Infected Humans

“…They are characterized by a lipobox motif that is crucial for initiation of lipid modifications. The structure responsible for the immunological activity is located in the NH 2 terminal triacylated lipopeptide region (47)(48)(49). Lipoproteins have been extensively found in both Gram-positive and -negative bacteria as well as in Treponema pallidum (50), Mycoplasma species (51), and Borrelia burgdorferi (52).…”

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

“…The M. tuberculosis genome encodes approximately 100 lipoproteins (Rezwan et al, 2007a;Sutcliffe & Harrington, 2004). Some contribute to immunopathogenesis of tuberculosis via TLR2 (Bigi et al, 2004;Brightbill et al, 1999), while other lipoproteins have protective properties and are considered to be tuberculosis vaccine candidates (Romano et al, 2006;Wang et al, 2007).…”

Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice

“…Remarkably, both BCG and Mtb MVs showed a prominent component of lipoproteins representing 20% and 10% of the total proteins, respectively (Tables 1 and 2). Since lipoproteins typically represent between 1% and 2% of mycobacterial genomes (20), this represented a major enrichment in the MVs. In order to experimentally confirm this enrichment in lipoproteins in MVs of BCG and Mtb, we analyzed the protein profiles of cellular lysates of these bacteria grown under the same culture conditions that were used for generation of MVs (Supplemental Tables 4 and 5).…”