title: Mycolactone reveals the substrate-driven complexity of Sec61-dependent transmembrane protein biogenesis.
abstract: Mycolactone is the exotoxin virulence factor produced byMycobacterium 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.
authors.affiliation: Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Michael Smith Building, Manchester M13 9PT, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: McKenna
authors.affiliation: Department of Microbial Sciences, School of Bioscience and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Simmonds
authors.affiliation: Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Michael Smith Building, Manchester M13 9PT, UK stephen.high@manchester.ac.uk.
authors.forename: Stephen
authors.identifier: 0000-0002-4532-8152
authors.initials: S
authors.lastname: High
mesh_terms: D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects*; D000072417:Protein Domains; D000069816:SEC Translocation Channels / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D018942:Macrolides; D008565:Membrane Proteins; D000069816:SEC Translocation Channels; D019010:Vascular Cell Adhesion Molecule-1; C117218:mycolactone
keywords: Endoplasmic reticulum; Membrane protein; Mycobacterium ulcerans; Mycolactone; Protein translocation; Sec61