What is it about?
Crosstalk between cell death programs confers appropriate host anti-infection immune responses, but how pathogens co-opt host molecular switches of cell death pathways to reprogram cell death modalities for facilitating infection remains largely unexplored. We identify Mce3C as a pathogenic cell death regulator secreted by Mycobacterium tuberculosis (Mtb), which inhibits host cathepsin B, a lysosome-derived non-caspase protease, to suppress host apoptosis while promoting necroptosis, hence exacerbating host immunopathology and facilitating bacterial survival.
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Why is it important?
Mammalian hosts coordinate various cell death pathways as part of defense system against pathogens including Mtb, which causes tuberculosis, a major lung infectious disease featured with lung inflammation and necrosis. Our findings reveal a pathogenic strategy by which Mtb Mce3C suppresses host lysosomal protease cathepsin B to modulate cell death modalities for promoting infection, thus providing a potential anti-tuberculosis treatment via targeting the Mce3C-cathepsin B interface.
Perspectives
Our findings unravel a previous unrecognized role of cathepsin B, which acts as a lysosome-derived non-caspase protease, in decision-making process underlying the host cell death upon infections, expanding our understanding of the elaborate crosstalk among cell death pathways. Also, our data reveal a pathogenic strategy by which the bacteria manipulate host lysosomal protease activity-dependent plasticity between cell death pathways to exacerbate host immunopathology and promote infection. This insight provides theoretical basis for developing anti-TB therapies by targeting the host-pathogen interaction at the cell death-immune response interface.
Cui Hua Liu
Institute of Microbiology, Chinese Academy of Sciences
Read the Original
This page is a summary of: A bacterial effector manipulates host lysosomal protease activity–dependent plasticity in cell death modalities to facilitate infection, Proceedings of the National Academy of Sciences, February 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2406715122.
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