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The ESX-1 Substrate PPE68 Has a Key Function in ESX-1-Mediated Secretion in Mycobacterium marinum
Merel P M Damen1, Aniek S Meijers2, Esther M Keizer1
1Section of Molecular Microbiology, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Mbio
|November 21, 2022
Summary
Mycobacterium marinum uses the ESX-1 secretion system for virulence. The PPE68 protein is crucial for secreting other essential substrates like EsxA and EspE, revealing a secretion hierarchy.
Area of Science:
- Microbiology
- Molecular Biology
- Pathogenesis
Background:
- Pathogenic mycobacteria, including Mycobacterium tuberculosis and Mycobacterium marinum, utilize type VII secretion systems (T7SSs), specifically the ESX-1 subtype, for virulence.
- The ESX-1 system secretes various substrates (Esx, PE, PPE, Esp proteins), some forming heterodimers, but their functions are difficult to study due to codependent secretion.
- ESX-1-mediated secretion is critical for mycobacterial intracellular survival, involving phagosomal rupture and host cytosol translocation.
Purpose of the Study:
- To elucidate the role of the ESX-1 substrate PPE68 in the secretion pathway of Mycobacterium marinum.
- To investigate the codependency and hierarchy among ESX-1 substrates.
- To propose a mechanistic model for PPE68's function in ESX-1-mediated secretion.
Main Methods:
- Investigated the secretion of ESX-1 substrates in Mycobacterium marinum.
- Analyzed the interaction of PPE68 with its partner PE and the EspG1 chaperone.
- Examined the effect of mutations and interference with protein binding on substrate secretion.
Main Results:
- PPE68 is essential for the secretion of immunogenic substrates EsxA and EspE via the ESX-1 system.
- Cell-associated PPE68 forms a complex with PE and EspG1; EspG1 binding is critical for PPE68 export and subsequent secretion of EsxA and EspE.
- PPE68 secretion is independent of EsxA, establishing a secretion hierarchy, and its C-terminal domain specifically mediates EspE secretion.
Conclusions:
- PPE68 plays a central, hierarchical role in ESX-1-mediated secretion, coordinating the export of multiple substrates.
- Distinct domains of PPE68 are responsible for the secretion of different ESX-1 substrates, highlighting functional specialization.
- Understanding this codependent secretion mechanism is key to deciphering T7SS functions and the virulence strategies of Mycobacterium tuberculosis.
