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

Merel P M Damen, Trang H Phan, Roy Ummels, Alba Rubio-Canalejas, Wilbert Bitter, Edith N G Houben

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Abstract

Bacterial type VII secretion systems (T7SSs) secrete a wide range of extracellular proteins that play important roles in bacterial viability and in interactions of pathogenic mycobacteria with their hosts. Mycobacterial T7SSs consist of five subtypes, ESX-1-5, and have four substrate classes, namely, Esx, PE, PPE, and Esp proteins. At least some of these substrates are secreted as heterodimers. Each ESX system mediates the secretion of a specific set of Esx, PE, and PPE proteins, raising the question how these substrates are recognized in a system-specific fashion. For the PE/PPE heterodimers, it has been shown that they interact with their cognate EspG chaperone and that this chaperone determines the designated secretion pathway. However, both structural and pulldown analyses have suggested that EspG cannot interact with the Esx proteins. Therefore, the determining factor for system specificity of the Esx proteins remains unknown. Here, we investigated the secretion specificity of the ESX-1 substrate pair EsxB_1/EsxA_1 in Mycobacterium marinum While this substrate pair was hardly secreted when homologously expressed, it was secreted when co-expressed together with the PE35/PPE68_1 pair, indicating that this pair could stimulate secretion of the EsxB_1/EsxA_1 pair. Surprisingly, co-expression of EsxB_1/EsxA_1 with a modified PE35/PPE68_1 version that carried the EspG5 chaperone-binding domain, previously shown to redirect this substrate pair to the ESX-5 system, also resulted in redirection and co-secretion of the Esx pair via ESX-5. Our results suggest a secretion model in which PE35/PPE68_1 determines the system-specific secretion of EsxB_1/EsxA_1.

Original languageEnglish
Pages (from-to)5960-5969
Number of pages10
JournalJournal of Biological Chemistry
Volume295
Issue number18
DOIs
Publication statusPublished - 1 May 2020

Bibliographical note

Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Funding

This work was supported by VIDI Grant 864.12.006 (to T. H. P. and E. N. G. H.) and ALW Open Grant ALWOP.319 (to M. P. M. D.) both from the Nether-lands Organization of Scientific Research. The authors declare that they have no conflicts of interest with the contents of this article. This article contains Tables S1–S3 and Figs. S1–S4. 1 These authors contributed equally to this work. 2To whom correspondence should be addressed. E-mail: e.n.g.houben@ vu.nl. This work was supported by VIDI Grant 864.12.006 (to T. H. P. and E. N. G. H.) and ALW Open Grant ALWOP.319 (to M. P. M. D.) both from the Netherlands Organization of Scientific Research.*%blankline%*

FundersFunder number
Nether-lands Organization of Scientific Research
Netherlands Organization of Scientific Research
VIDI864.12.006

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