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Review
. 2016 Jan;18(1):17-29.
doi: 10.1111/cmi.12547.

Recent advances: role of mycolactone in the pathogenesis and monitoring of Mycobacterium ulcerans infection/Buruli ulcer disease

Affiliations
Review

Recent advances: role of mycolactone in the pathogenesis and monitoring of Mycobacterium ulcerans infection/Buruli ulcer disease

Fred Stephen Sarfo et al. Cell Microbiol. 2016 Jan.

Abstract

Infection of subcutaneous tissue with Mycobacterium ulcerans can lead to chronic skin ulceration known as Buruli ulcer. The pathogenesis of this neglected tropical disease is dependent on a lipid-like toxin, mycolactone, which diffuses through tissue away from the infecting organisms. Since its identification in 1999, this molecule has been intensely studied to elucidate its cytotoxic and immunosuppressive properties. Two recent major advances identifying the underlying molecular targets for mycolactone have been described. First, it can target scaffolding proteins (such as Wiskott Aldrich Syndrome Protein), which control actin dynamics in adherent cells and therefore lead to detachment and cell death by anoikis. Second, it prevents the co-translational translocation (and therefore production) of many proteins that pass through the endoplasmic reticulum for secretion or placement in cell membranes. These pleiotropic effects underpin the range of cell-specific functional defects in immune and other cells that contact mycolactone during infection. The dose and duration of mycolactone exposure for these different cells explains tissue necrosis and the paucity of immune cells in the ulcers. This review discusses recent advances in the field, revisits older findings in this context and highlights current developments in structure-function studies as well as methodology that make mycolactone a promising diagnostic biomarker.

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Figures

Figure 1
Figure 1
Molecular structure of mycolactone A/B. The chemical structure of mycolactone A/B has a core cyclic lactone ring (C1–C11) and two polyketide‐derived highly unsaturated acyl side chains. The upper ‘Northern’ chain consists of C12–C20 and the longer ‘Southern’ chain is numbered C1′–C16′. The numbering reflects the natural synthetic pathway of mycolactone by the polyketide synthase enzymes in MU. Under common laboratory conditions and light, mycolactone exists as spontaneously forming geometric isomers centered around the double bond at C4′C5′ (indicated by the wavy line between C5′ and C6′) in a 3:2 ratio. The structure of the variant mycolactone‐like molecule 5b is also shown; this lacks the C8 methyl and the Northern chain.
Figure 2
Figure 2
Mycolactone causes hyperactivation of WASP. WASP and N‐WASP are modular scaffolding proteins that exist in auto‐inhibited conformation in which the VCA (verprolin‐cofilin‐acidic) domain (yellow) is occluded by an intramolecular interaction (dotted line; a). Activation of WASP and N‐WASP occurs by disruption of the intermolecular interaction by a variety of ligands including the cell cycle regulator CDC42 and binding/activation of the Arp2/3 complex (b). The VCA domain of WASP, Arp2/3 complex and G‐actin forms a nucleating centre for incorporation of actin subunits for growth of actin filaments (c, d, e). Actin polymerisation and formation of cytoskeleton is crucial for endocytosis, cell‐to‐cell adhesion and migration of cells. Mycolactone hijacks and disrupts the auto‐inhibited state of WASP/N‐WASP (f). This forces WASP into the activated state with Arp2/3 bound (g). Mycolactone causes increases in the rate of Arp2/3‐mediated actin assembly, outside of normal cellular control (h) Unregulated actin polymerisation leads to defective cytoskeleton formation and loss cell adhesion and apoptosis (i, j).
Figure 3
Figure 3
Mycolactone inhibits the co‐translational translocation of proteins via Sec61. Sec61‐dependent, ER‐transiting proteins are derived from mRNAs (a) and usually have a signal peptide sequence at the amino terminus (b). Once this is formed, translation pauses and the signal peptide is recognized by the SRP (not shown), which transports the ribosome/mRNA/nascent peptide complex to the Sec61 complex at the ER membrane (c). The hydrophobic signal peptide interacts with Sec61 and translation continues, directly into the ER lumen (d); a process further facilitated by chaperones such as BiP (not shown). A similar process occurs for transmembrane proteins (TNF), monotypic proteins (COX‐2) and conventionally secreted proteins (IL‐6). In the presence of mycolactone, translocation cannot occur (e) so translation takes place in the cytoplasm instead (f), and the proteins, recognized by the cell as being in the wrong compartment, are destroyed almost immediately by the 26S proteasome (g). This means that induced proteins can never be detected, and constitutive proteins are lost from the cell as they cannot be replaced during normal protein recycling.

References

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