Lipoproteins of Gram-Positive Bacteria: Key Players in the Immune Response and Virulence - PubMed (original) (raw)
Review
Lipoproteins of Gram-Positive Bacteria: Key Players in the Immune Response and Virulence
Minh Thu Nguyen et al. Microbiol Mol Biol Rev. 2016.
Abstract
Since the discovery in 1973 of the first of the bacterial lipoproteins (Lpp) in Escherichia coli, Braun's lipoprotein, the ever-increasing number of publications indicates the importance of these proteins. Bacterial Lpp belong to the class of lipid-anchored proteins that in Gram-negative bacteria are anchored in both the cytoplasmic and outer membranes and in Gram-positive bacteria are anchored only in the cytoplasmic membrane. In contrast to the case for Gram-negative bacteria, in Gram-positive bacteria lipoprotein maturation and processing are not vital. Physiologically, Lpp play an important role in nutrient and ion acquisition, allowing particularly pathogenic species to better survive in the host. Bacterial Lpp are recognized by Toll-like receptor 2 (TLR2) of the innate immune system. The important role of Lpp in Gram-positive bacteria, particularly in the phylum Firmicutes, as key players in the immune response and pathogenicity has emerged only in recent years. In this review, we address the role of Lpp in signaling and modulating the immune response, in inflammation, and in pathogenicity. We also address the potential of Lpp as promising vaccine candidates.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
Figures
FIG 1
Variable structures of the lipid moiety of lipoproteins (Lpp). In most Gram-negative bacteria Lpp are triacylated due to the thioether-linked diacyl glycerol residue and an acyl group at the N terminus of cysteine (A), in some low-GC Gram-positive bacteria the _N_-acyl group is missing (B), and in representatives of the lactic acid bacterial group an _N_-acyl-_S_-monoacylglyceryl-cysteine (named the lyso structure) has been identified (C). *, chiral center.
FIG 2
Membrane incorporation of mature Lpp and unmodified/unprocessed pre-Lpp. (A) Matured and processed Lpp are localized with the triacyl or diacyl groups of the lipid moiety in the outer leaflet of the cytoplasmic membrane. (B) In the Δ_lgt_ mutant, the gene encoding the diacylglyceryl transferase enzyme is deleted; this mutant is unable to carry out the lipidation at the cysteine residue, and because of this lack of modification, the lipoprotein leader peptidase (Lsp) cannot process the signal peptide because this enzyme works only with modified pre-Lpp. (C) In the Δ_lsp_ mutant, the gene encoding the lipoprotein leader peptidase (Lsp) is deleted; in this mutant, lipidation at the cysteine residue can occur, but there is no processing of the signal peptide. Blue circles, amino acids of the lipo-signal peptide; blue wavy lines, protein part protruding into the cell wall; red-circled “C,” cysteine residues; zigzag lines, O- or N-acylated fatty acids.
FIG 3
Skin immune tolerance is caused by di- but not triacylated Lpp. Diacylated Lpp are sensed by the TLR2/TLR6 heterodimer, while triacylated Lpp are sensed by the TLR2/TLR1 heterodimer. Originally it was thought that the degree of acylation does not make much difference in signaling. However, diacylated Lpp such as Pam2Cys caused a multifold-higher induction of IL-6 than that caused by Pam3Cys in skin resident cells. IL-6 expands into mouse sera, causing induction of suppressive MDSCs derived from normal human peripheral blood mononuclear and granulocytic cells. Finally, the accumulation of MDSCs induces immune suppression. Lpp, lipoproteins/lipopeptides; MyD88, myeloid differentiation primary response protein 88; MDSCs, myeloid-derived suppressor cells; NF-κB, nuclear factor kappa-light-chain enhancer; NOD, nucleotide binding oligomerization domain-containing protein; RIP2, receptor-interacting serine/threonine protein kinase 2.
FIG 4
Possible mechanisms for the synergistic immune stimulation of TLR2 and NOD2 ligands. Stimulation with di- and triacylated Lpp triggers the TLR2-MyD88-dependent signaling pathway, resulting in NF-κB activation and induction of proinflammatory cytokines. The latter, particularly TNF-α, upregulate NOD expression as well as oligopeptide transporters, e.g., hPepT1 and SCL15A4, that also transport NOD agonists. PGN is also taken up in an endocytosis-like process, from where it can be translocated into cytoplasm by the endosomal transporter SCL15A4. How NODs are recruited to the plasma membrane is unknown. Lpp not only act as TLR2 agonists but are also able to cause membrane scrambling; whether this effect contributes to signaling or to facilitating PGN uptake is unknown. Both TLR2 and NOD activation lead finally to NF-κB activation, but the downstream adaptor molecules, RIP2 and MyD88, are different, thus excluding competition for a common adaptor protein and allowing synergistic NF-κB activation. PGN, peptidoglycan; Lpp, lipoproteins/lipopeptides; MyD88, myeloid differentiation primary response protein 88; NF-κB, nuclear factor kappa-light-chain enhancer; NOD, nucleotide binding oligomerization domain-containing protein; RIP2, receptor-interacting serine/threonine protein kinase 2.
FIG 5
Possible mechanism for the antagonistic effect of Lpp and RNA in innate immune stimulation in monocytes and macrophages. The induction of IFN-β production by whole bacteria in human primary monocytes and monocyte-derived macrophages (MDMs) is triggered by S. aureus RNA sensed by TLR7 and TLR8, which activates the TAK1-IKKβ-IRF5 signaling pathway. TLR2 activation by Lpp suppresses the RNA-induced production of IFN-β. As both TLR2 and TLR8 use the same adaptor molecule MyD88 in TAK1-dependent and TAK1-independent pathways, a depletion of MyD88 is the consequence (99). Another explanation for TLR2's overruling the TLR8 signaling is their different locations; Lpp can immediately activate TLR2 at the host cell surface, while TLR8 activation usually affords phagocytosis and phagolysosomally mediated release of RNA, which is unfavorable in the competition for MyD88. IKKβ, a serine kinase which plays a key role in the NF-κB signaling pathway by phosphorylating inhibitors in the inhibitor/NF-κB complex; IRF5, interferon regulatory factor 5; Lpp, lipoproteins/lipopeptides; MyD88, myeloid differentiation primary response protein 88; NF-κB, nuclear factor kappa-light-chain enhancer; ssRNA, single-strand RNA; TAK1, ubiquitin-dependent kinase of MKK and IKK. TLR7 and TLR8 are activated by ribonucleoside analogs.
References
- Braun V, Rehn K. 1969. Chemical characterization, spatial distribution and function of a lipoprotein (murein-lipoprotein) of the E. coli cell wall. The specific effect of trypsin on the membrane structure. Eur J Biochem 10:426–438. - PubMed
- Hantke K, Braun V. 1973. Covalent binding of lipid to protein. Diglyceride and amide-linked fatty acid at the N-terminal end of the murein-lipoprotein of the Escherichia coli outer membrane. Eur J Biochem 34:284–296. - PubMed
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