Abstract
ABSTRACTMycolactone 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.
Highlights
The exotoxin mycolactone is produced by Mycobacterium ulcerans and is the causative agent of Buruli ulcer; a disease characterised by necrotic skin ulcers and immunosuppression (George et al, 1999; Silva et al, 2009; Walsh et al, 2011)
As a type I transmembrane protein (TMP), successful insertion of CD3δ is indicated by modification of its two endogenous N-glycosylation sites contained within the region N-terminal to the transmembrane domain (TMD) (Fig. 1A)
In this study, we explore the inhibitory mechanism of mycolactone at the Sec61 translocon by investigating the integration of three distinct classes of single-pass transmembrane proteins (TMPs)
Summary
The exotoxin mycolactone is produced by Mycobacterium ulcerans and is the causative agent of Buruli ulcer; a disease characterised by necrotic skin ulcers and immunosuppression (George et al, 1999; Silva et al, 2009; Walsh et al, 2011). Some nascent secretory proteins insert into the Sec complex with their N-terminal signal sequence in a looped, or ‘hairpin’, conformation (Mothes et al, 1994; Voorhees and Hegde, 2016), and this insertion precedes translocation of their mature domain into the ER lumen (Görlich et al, 1992). These sequences must be sufficiently hydrophobic to destabilise the hydrophobic interactions between transmembrane domains 2 and 7 of the core Sec61α subunit (of which there are two human isoforms, SEC61A1 and SEC61A2), and thereby open what is known as the ‘lateral gate’ (Trueman et al, 2012; Voorhees and Hegde, 2016). Mycolactone does not interfere with SRPdependent delivery of secretory proteins to the ER but rather prevents their co-translational translocation, most likely by stabilising the Sec complex in a closed conformation (McKenna et al, 2016) by interacting near the lumenal plug of Sec61α (Baron et al, 2016)
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