Pleiotropic molecular effects of the<i>Mycobacterium ulcerans</i>virulence factor mycolactone underlying the cell death and immunosuppression seen in Buruli ulcer

Hall, Belinda S.; Simmonds, Rachel E.

doi:10.1042/bst20130133

Cited by 51 publications

(53 citation statements)

References 54 publications

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“…Notably, most of the type I TMPs that are mycolactone-sensitive at a cellular level have N-terminal domains of a similar or larger size (cf. Hall and Simmonds, 2014), including thrombomodulin, consistent with the previously suggested mycolactone-dependent inhibition of its ER translocation (Ogbechi et al, 2015). Our limited in vitro analysis of type II TMPs suggests that their membrane integration is highly sensitive to mycolactone, and this is consistent with previous observations using TNFα (Hall et al, 2014).…”

Section: Discussionsupporting

confidence: 86%

“…Both secreted mediators, such as cytokines and chemokines, as well as TMPs, such as receptors, are under-produced in cells treated with mycolactone, while cytoplasmic substrates appear to be consistently unaffected (Coutanceau et al, 2007; Hall and Simmonds, 2014; Simmonds et al, 2009). Our current study suggests that type I TMPs with N-terminal domains of more than ∼100 residues are highly sensitive to mycolactone treatment in vitro .…”

Section: Discussionmentioning

confidence: 99%

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Mycolactone reveals the substrate-driven complexity of Sec61-dependent transmembrane protein biogenesis

McKenna

Simmonds

High

2017

Journal of Cell Science

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Mycolactone is the exotoxin virulence factor produced by Mycobacterium ulcerans, the pathogen responsible for Buruli ulcer. The skin lesions and immunosuppression that are characteristic of this disease result from the action of mycolactone, which targets the Sec61 complex and inhibits the co-translational translocation of secretory proteins into the endoplasmic reticulum. In this study, we investigate the effect of mycolactone on the Sec61-dependent biogenesis of different classes of transmembrane protein (TMP). Our data suggest that the effect of mycolactone on TMP biogenesis depends on how the nascent chain initially engages the Sec61 complex. For example, the translocation of TMP lumenal domains driven by an N-terminal cleavable signal sequence is efficiently inhibited by mycolactone. In contrast, the effect of mycolactone on protein translocation that is driven solely by a non-cleavable signal anchor/transmembrane domain depends on which flanking region is translocated. For example, while translocation of the region N-terminal to a signal anchor/transmembrane domain is refractive to mycolactone, C-terminal translocation is efficiently inhibited. Our findings highlight the diversity of Sec61-dependent translocation and provide a molecular basis for understanding the effect of mycolactone on the biogenesis of different TMPs.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Mycolactone reveals the substrate-driven complexity of Sec61-dependent transmembrane protein biogenesis

McKenna

Simmonds

High

2017

Journal of Cell Science

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“…The intricacies of translation and its control in disease states means that, even when translational control is implicated in disease progression, the mode of such control can be elusive. Hall and Simmonds [23] expertly summarize our knowledge of mycolactone action on mammalian cells. This polyketide lactone is produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer, a severe disease characterized by the development of chronic necrotizing skin ulcers at the sites of infection.…”

Section: Translational Control: Dysregulation and Diseasementioning

confidence: 99%

Control and regulation of mRNA translation

Mead

Masterton

Haar

et al. 2014

Biochemical Society Transactions

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Translational control is central to the gene expression pathway and was the focus of the 2013 annual Translation UK meeting held at the University of Kent. The meeting brought together scientists at all career stages to present and discuss research in the mRNA translation field, with an emphasis on the presentations on the research of early career scientists. The diverse nature of this field was represented by the broad range of papers presented at the meeting. The complexity of mRNA translation and its control is emphasized by the interdisciplinary research approaches required to address this area with speakers highlighting emerging systems biology techniques and their application to understanding mRNA translation and the network of pathways controlling it.

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“…45,46 Recent evidence has revealed that mycolactone exerts a profound effect on protein secretion by blocking the co-translational translocation of a plethora of proteins that pass through the endoplasmic reticulum for secretion or placement in cell membranes. 47,48 It is noteworthy that many of these proteins are important in wound healing, and we hypothesize that the rate of healing of ulcers under antibiotic treatment may be significantly impacted by the rate of clearance of mycolactone from tissues. Studies are underway to evaluate the synergy between tissue levels of mycolactone, bacterial load, and rate of wound healing in BUD in humans.…”

Section: Diagnostic Confirmationmentioning

confidence: 99%

Buruli ulcer: wound care and rehabilitation

Frimpong¹,

Duah²,

Wansbrough‐Jones³

et al. 2016

CWCMR

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Buruli ulcer caused by Mycobacterium ulcerans is a neglected tropical disease characterized by extensive ulceration involving predominantly the upper and lower limbs of patients. The disease is common in rural tropical communities in West and Central Africa, where access to proper health care is limited. Pathogenesis of the characteristic painless ulcers is linked to the elaboration by M. ulcerans of a lipid toxin called mycolactone that has potent cytopathic, immunosuppressive, and analgesic effects on a host of cells in cutaneous tissues. Mycolactone is known to profoundly inhibit secretion of a plethora of proteins that are essential for wound healing. Even though a combination antibacterial therapy of streptomycin and rifampicin for 8 weeks is effective for treatment, it relies on good and appropriate wound management to prevent secondary bacterial infections and improve healing. Evidence-based interventions for wound care in Buruli ulcer disease are often lacking and have relied on expert advice and recommendations. Surgical interventions are limited to debridement of necrotic tissue and grafting of extensive ulcers, usually after antibiotic therapy. Patients' rehabilitation is an important component of care to reduce disabilities associated with the disease and proper integration into the community after treatment.

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Pleiotropic molecular effects of theMycobacterium ulceransvirulence factor mycolactone underlying the cell death and immunosuppression seen in Buruli ulcer

Cited by 51 publications

References 54 publications

Mycolactone reveals the substrate-driven complexity of Sec61-dependent transmembrane protein biogenesis

Mycolactone reveals the substrate-driven complexity of Sec61-dependent transmembrane protein biogenesis

Control and regulation of mRNA translation

Buruli ulcer: wound care and rehabilitation

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