Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease

Abstract

Infection with Mycobacterium ulcerans results in a necrotising skin disease known as a Buruli ulcer, the pathology of which is directly linked to the bacterial production of the toxin mycolactone. Recent studies have identified the protein translocation machinery of the endoplasmic reticulum (ER) membrane as the primary cellular target of mycolactone, and shown that the toxin binds to the core subunit of the Sec61 complex. Mycolactone binding strongly inhibits the capacity of the Sec61 translocon to transport newly synthesised membrane and secretory proteins into and across the ER membrane. Since the ER acts as the entry point for the mammalian secretory pathway, and hence regulates initial access to the entire endomembrane system, mycolactone-treated cells have a reduced ability to produce a range of proteins including secretory cytokines and plasma membrane receptors. The global effect of this molecular blockade of protein translocation at the ER is that the host is unable to mount an effective immune response to the underlying mycobacterial infection. Prolonged exposure to mycolactone is normally cytotoxic, since it triggers stress responses activating the transcription factor ATF4 and ultimately inducing apoptosis.

Natural products as modulators of eukaryotic protein secretion

“…36 For a comprehensive review on mycolactone mechanisms, see ref. 37. This bacteria harbors a megaplasmid that contains the polyketide synthetase genes required for mycolactone biosynthesis.…”

Structure of the Inhibited State of the Sec Translocon

“…Of the current inhibitors, mycolactone ( Figure 1 A) is the most potent ( Hall et al., 2014 ). This diffusible lipid-like exotoxin is synthesized by the Buruli ulcer pathogen Mycobacterium ulcerans ( Demangel and High, 2018 ; Yotsu et al., 2018 ) and forms a stable complex with Sec61α ( Baron et al., 2016 ). It prevents co-translational translocation of secretory proteins, including inflammatory mediators and cytokines, at nanomolar concentrations ( Baron et al., 2016 ; Hall et al., 2014 ; McKenna et al., 2016 ) and blocks Sec61-dependent insertion of many transmembrane proteins ( Baron et al., 2016 ; McKenna et al., 2017 ).…”

SMIM1, carrier of the Vel blood group, is a tail-anchored transmembrane protein and readily forms homodimers in a cell-free system

“…However, in 2015 Arnaud et al [7] published data strongly suggesting that SMIM1 orients itself as a type II transmembrane protein with a short extracellular C-terminus of approximately five to ten amino acids, on which the Vel antigen is carried. This topology is reminiscent of a distinct group of integral membrane proteins known as tail-anchored proteins [9,10] ( Figure 1B).…”

“…Although Glycophorin A is a type I transmembrane protein, guided to the ER membrane by an N-terminal cleavable signal sequence, Glycophorin C lacks such a signal sequence, but still assumes a transmembrane topology where its N-terminus is located outside the plasma membrane. This latter topology is sometimes classified as a type III transmembrane protein [9,10]. On this basis, our initial prediction was that SMIM1 may also be a type III protein, an orientation that would also allow for the major portion of the protein to be displayed on the outside of the cell thereby providing multiple immunogenic sites that might explain the diversity between anti-Vel antibodies from different individuals [11].…”