Mycobacterium tuberculosis Toxin CpnT Is an ESX-5 Substrate and Requires Three Type VII Secretion Systems for...

Area of Science:

• Microbiology
• Molecular Biology
• Pathogenesis

Background:

• Tuberculosis is caused by Mycobacterium tuberculosis, an intracellular pathogen.
• CpnT is a recently identified secreted toxin of M. tuberculosis responsible for host cell necrosis.
• The secretion pathway for CpnT remained unknown until this study.

Purpose of the Study:

• To elucidate the secretion pathway of the Mycobacterium tuberculosis toxin CpnT.
• To identify the specific type VII secretion (T7S) systems involved in CpnT secretion.
• To understand the interplay between T7S systems during intracellular secretion of CpnT.

Main Methods:

• Analysis of CpnT mutants with disruptions in secretion motifs.
• Investigating CpnT secretion in Mycobacterium marinum using different ESX systems.
• Assessing CpnT secretion during macrophage infection and by coinfection experiments.

Main Results:

• CpnT secretion is dependent on a specific YxxxE motif, characteristic of T7S substrates.
• In axenic culture, CpnT is exclusively secreted by the ESX-5 system.
• Intracellular CpnT secretion during infection requires functional ESX-1, ESX-4, and ESX-5 systems.

Conclusions:

• CpnT is a substrate of mycobacterial type VII secretion systems.
• Three distinct T7S systems (ESX-1, ESX-4, ESX-5) are essential for intracellular CpnT secretion.
• This study reveals a novel, coordinated mechanism of T7S system utilization by a bacterial toxin during infection.