A bacterial effector manipulates host lysosomal protease activity-dependent plasticity in cell death modalities to facilitate infection

Crosstalk between cell death programs confers appropriate host anti-infection immune responses, but how pathogens remodel this network to facilitate their infections remain largely unclear. Here, we identify mammalian cell entry 3C (Mce3C) as a key regulator of host cell death from Mycobacterium tuberculosis (Mtb), which causes tuberculosis featured with lung inflammation and necrosis. Mce3C binds host lysosomal protease cathepsin B (CTSB), which acts as a decision-maker of cell death modalities, to inhibit the protease activity of CTSB towards BH3-interacting domain death agonist (BID) and receptor-interacting protein kinase 1 (RIPK1), thus preventing the production of pro-apoptotic truncated BID (tBID) while maintaining the abundance of pro-necroptotic RIPK1. Disrupting the Mce3C-CTSB interaction promotes host apoptosis and suppresses necroptosis with attenuated Mtb survival and mitigated lung inflammation in mice. These findings reveal a unique strategy by which the pathogen manipulates host lysosomal protease activity-dependent plasticity between cell death pathways to promote infection and pathogenicity.