8.C.7. The Mycolactone (Mycolactone) Family
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. The effects of mycolactone on the Sec61-dependent biogenesis of different classes of transmembrane proteins (TMP) differ (McKenna et al. 2017). Thus, 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, but 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. While translocation of the region N-terminal to a signal anchor/transmembrane domain is refractive to mycolactone, C-terminal translocation is efficiently inhibited. The diversity of Sec61-dependent translocation s illustrated (McKenna et al. 2017).