Lipoproteins of bacterial pathogens

Abstract

Bacterial lipoproteins are a set of membrane proteins with many different functions. Due to this broad-ranging functionality, these proteins have a considerable significance in many phenomena, from cellular physiology through cell division and virulence. Here we give a general overview of lipoprotein biogenesis and highlight examples of the roles of lipoproteins in bacterial disease caused by a selection of medically relevant Gram-negative and Gram-positive pathogens: Mycobacterium tuberculosis, Streptococcus pneumoniae, Borrelia burgdorferi, and Neisseria meningitidis. Lipoproteins have been shown to play key roles in adhesion to host cells, modulation of inflammatory processes, and translocation of virulence factors into host cells. As such, a number of lipoproteins have been shown to be potential vaccines. This review provides a summary of some of the reported roles of lipoproteins and of how this knowledge has been exploited in some cases for the generation of novel countermeasures to bacterial diseases.

FIG. 1.

Biosynthesis of bacterial lipoproteins. (A to C) Two-step biosynthetic pathway in Gram-positive bacteria. (A to D) Three-step biosynthetic pathway in Gram-negative bacteria. (A) The precursor of lipoproteins is the preprolipoprotein, with an N-terminal signal peptide possessing a characteristic consensus sequence of the lipobox. (B) During lipoprotein maturation, the thiol group of the invariant cysteine in the lipobox is modified by a diacylglyceryl moiety by lipoprotein diacylglyceryl transferase (Lgt), which serves as a membrane anchor. (C) After lipidation, lipoprotein signal peptidase (Lsp) cleaves the signal peptide, leaving the cysteine as the new amino-terminal residue forming the mature lipoprotein in Gram-positive bacteria. (D) In Gram-negative and some Gram-positive bacteria, the mature lipoprotein has an additional amide-linked fatty acid at the N-terminal cysteine residue attached by lipoprotein N-acyl transferase (Lnt). Amino acid residues at position +2, +3, and +4 have a role in membrane localization of Gram-negative bacterial lipoproteins.

FIG. 2.

Localization of bacterial lipoproteins. (A) In Gram-negative bacteria, lipoproteins are attached to the cytoplasmic membrane, the extracellular or peripheral side of the outer membrane. (B) In Gram-positive bacteria, lipoproteins are anchored to the extracellular surface of the cytoplasmic membrane and also to the unique mycolate-based lipid layer of the cell wall of Mycobacterium tuberculosis. OM, outer membrane; PG, peptidoglycan; CM, cytoplasmic membrane; AG, arabino-galactan; ML, mycolic acid layer; C, capsule-like material; N, N-terminal.