Limna - Lausanne Integrative Metabolism Nutrition Alliance

SEMINAR

Wednesday 8th August 2018
10h30 - Conference room AI 1153 (*)- EPFL - Lausanne

Mycolactone, a pathogen-derived inhibitor of Sec61 with immunosuppressive properties


Jean-David MOREL 

Immunobiology of Infection Unit, Institut Pasteur, Paris, France

Host: Prof. Johan Auwerx

(*) IMPORTANT NOTICE: All external participants have to pass through SV Reception/Welcome Desk to be able to access to AI 1153. Contact person to call at arrival at SV Reception Desk: Administrative Assistant: 39522.

Abstract

Mycolactone is a diffusible macrolide produced by the human pathogen Mycobacterium ulcerans, the causative agent of necrotic skin lesions called Buruli ulcers. In addition to displaying cytotoxic properties locally, mycolactone down-regulates the host immune responses. In vitro work had indicated that mycolactone blocks the co-translational translocation of secretory proteins into the endoplasmic reticulum (ER), leading to their cytosolic degradation by the ubiquitin:proteasome system. We demonstrated that mycolactone targets the alpha subunit of the Sec61 translocon (Sec61α). Using quantitative proteomics, we showed that Sec61 blockade impairs key immune processes, such as antigen presentation by dendritic cells, T cell activation and migration. These global analyses also revealed that mycolactone-driven Sec61 blockade triggers ER stress responses, eventually causing apoptotic cell death.