Abstract
Mycobacteria use the dedicated type VII protein secretion systems ESX-1 and ESX-5 to secrete virulence factors across their highly hydrophobic cell envelope. The substrates of these systems include the large mycobacterial PE and PPE protein families, which are named after their characteristic Pro-Glu and Pro-Pro-Glu motifs. Pathogenic mycobacteria secrete large numbers of PE/PPE proteins via the major export pathway, ESX-5. In addition, a few PE/PPE proteins have been shown to be exported by ESX-1. It is not known how ESX-1 and ESX-5 recognize their cognate PE/PPE substrates. In this work, we investigated the function of the cytosolic protein EspG(5), which is essential for ESX-5-mediated secretion in Mycobacterium marinum, but for which the role in secretion is not known. By performing protein co-purifications, we show that EspG(5) interacts with several PPE proteins and a PE/PPE complex that is secreted by ESX-5, but not with the unrelated ESX-5 substrate EsxN or with PE/PPE proteins secreted by ESX-1. Conversely, the ESX-1 paralogue EspG(1) interacted with a PE/PPE couple secreted by ESX-1, but not with PE/PPE substrates of ESX-5. Furthermore, structural analysis of the complex formed by EspG(5) and PE/PPE indicates that these proteins interact in a 1:1:1 ratio. In conclusion, our study shows that EspG(5) and EspG(1) interact specifically with PE/PPE proteins that are secreted via their own ESX systems and suggests that EspG proteins are specific chaperones for the type VII pathway.
Highlights
Pathogenic mycobacteria use the type VII secretion systems (T7SS) ESX-1 and ESX-5 to secrete virulence factors, but it is unknown how these systems recognize their cognate substrates
We investigated the function of the cytosolic protein EspG5, which is essential for ESX-5-mediated secretion in Mycobacterium marinum, but for which the role in secretion is not known
By performing protein co-purifications, we show that EspG5 interacts with several PPE proteins and a PE/PPE complex that is secreted by ESX-5, but not with the unrelated ESX-5 substrate EsxN or with PE/PPE proteins secreted by ESX-1
Summary
Pathogenic mycobacteria use the type VII secretion systems (T7SS) ESX-1 and ESX-5 to secrete virulence factors, but it is unknown how these systems recognize their cognate substrates. Mycobacteria use the dedicated type VII protein secretion systems ESX-1 and ESX-5 to secrete virulence factors across their highly hydrophobic cell envelope The substrates of these systems include the large mycobacterial PE and PPE protein families, which are named after their characteristic Pro-Glu and Pro-Pro-Glu motifs. Pathogenic mycobacteria, such as Mycobacterium tuberculosis, the causal agent of tuberculosis, secrete proteinaceous virulence factors These bacteria are surrounded by a unique diderm cell envelope that requires a specialized secretion pathway, known as the ESX or type VII secretion pathway, to facilitate protein export [2]. This signal does not discriminate among the various ESX pathways [9]
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