Dr. Edith N.G. Houben - Elucidating type VII secretion: the gateway through the unique mycobacterial cell envelope - IPBS-Toulouse, Hybrid Seminar (Seminar Room)

Tuberculosis (TB) is responsible for 1.4 million deaths annually, making the causative agent, Mycobacterium tuberculosis (Mtb), the deadliest bacterial pathogen worldwide. The challenge in combating TB is the absence of an effective vaccine and the emergence of extensive drug-resistance. To come up with urgently needed new concepts for new anti-TB therapeutics and prophylactics, a better understanding of how pathogenic mycobacteria function on a molecular level is essential. Mycobacteria have a unique and extremely hydrophobic cell envelope, consisting of two membranes. This complex structure serves as an efficient permeability barrier, essential for pathogenic mycobacteria to survive during infection, and also conferring intrinsic resistance to most antibiotics. While seemingly impenetrable, these bacteria use a set of type VII secretion systems (T7SSs) for the export of extracellular proteins that mediate crucial interactions with the host. We study how T7SSs are able to transport proteins across the mycobacterial cell envelope, while maintaining the integrity of this protective layer. Our latest achievement is the first high-resolution structure of a full T7SS membrane complex from Mtb. The structure describes a large 2.32 MDa assembly with an astonishing number of 165 transmembrane domains and a closed central secretion conduit.We are currently building on this knowledge to obtain a deeper understanding of substrate recognition by and subsequent transport through the elucidated membrane conduit. Elucidating T7SSs, as the potential weak spots of the mycobacterial cell envelope could lead to a step-change in anti-TB drug development.

Selected publications

• Structure and dynamics of a mycobacterial type VII secretion system. Bunduc CM, Fahrenkamp D, Wald J, Ummels R, Bitter W, Houben ENG, Marlovits TC. Nature. 2021 May;593(7859):445-448
• Modification of a PE/PPE substrate pair reroutes an Esx substrate pair from the mycobacterial ESX-1 type VII secretion system to the ESX-5 system. Damen MPM, Phan TH, Ummels R, Rubio-Canalejas A, Bitter W, Houben ENG. J Biol Chem. 2020 May 1;295(18):5960-5969
• Species-specific secretion of ESX-5 type VII substrates is determined by the linker 2 of EccC5. Bunduc CM, Ummels R, Bitter W, Houben ENG. Mol Microbiol. 2020 Jul;114(1):66-76
• A Chimeric EccB-MycP Fusion Protein is Functional and a Stable Component of the ESX-5 Type VII Secretion System Membrane Complex. van Winden VJC, Bunduc CM, Ummels R, Bitter W, Houben ENG. J Mol Biol. 2020 Feb 14;432(4):1265-1278
• Bacterial secretion chaperones: the mycobacterial type VII case. Phan TH, Houben ENG. FEMS Microbiol Lett. 2018 Sep 1;365(18):fny197
• Structure of the mycobacterial ESX-5 type VII secretion system membrane complex by single-particle analysis. Beckham KS, Ciccarelli L, Bunduc CM, Mertens HD, Ummels R, Lugmayr W, Mayr J, Rettel M, Savitski MM, Svergun DI, Bitter W, Wilmanns M, Marlovits TC, Parret AH, Houben EN. Nat Microbiol. 2017 Apr 10;2:17047
• Mycosins Are Required for the Stabilization of the ESX-1 and ESX-5 Type VII Secretion Membrane Complexes. van Winden VJ, Ummels R, Piersma SR, Jiménez CR, Korotkov KV, Bitter W, Houben EN. mBio. 2016 Oct 18;7(5):e01471-16.
• Essential Role of the ESX-5 Secretion System in Outer Membrane Permeability of Pathogenic Mycobacteria. Ates LS, Ummels R, Commandeur S, van de Weerd R, Sparrius M, Weerdenburg E, Alber M, Kalscheuer R, Piersma SR, Abdallah AM, Abd El Ghany M, Abdel-Haleem AM, Pain A, Jiménez CR, Bitter W, Houben EN. PLoS Genet. 2015 May 4;11(5):e1005190.