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 co-opt host molecular
switches of cell death pathways to reprogram cell death modalities for
facilitating infection remains largely unclear. Here, we identify
mammalian cell entry 3C (Mce3C) as a pathogenic cell death regulator
secreted by Mycobacterium tuberculosis (Mtb), which causes tuberculosis
featuring lung inflammation and necrosis. Mce3C binds host cathepsin B
(CTSB), a non-caspase protease acting as a lysosome-derived molecular
determinant of cell death modalities, to inhibit its protease activity
towards BH3-interacting domain death agonist (BID) and
receptor-interacting protein kinase 1 (RIPK1), thereby 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 while suppressing necroptosis with attenuated Mtb
survival and mitigated lung immunopathology in mice. Thus, pathogens
manipulate host lysosomal protease activity-dependent plasticity between
cell death pathways to promote infection and pathogenicity.