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

Zhe Lu; Yong Zhang; Yanzhao Zhong; Lihua Qiang; Pupu Ge; Zehui Lei; Mengyuan Zhao; Yingxu Fang; Bingxi Li; Jing Wang; Qiyao Chai; Cui Hua Liu

doi:10.1073/pnas.2406715122

Proceedings of the National Academy of Sciences

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

Z Zhe Lu (Chinese Academy of Sciences (CAS) Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences) Y Yong Zhang Y Yanzhao Zhong (Chinese Academy of Sciences (CAS) Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences) L Lihua Qiang (Chinese Academy of Sciences (CAS) Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences) P Pupu Ge (Chinese Academy of Sciences (CAS) Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences) Z Zehui Lei (Chinese Academy of Sciences (CAS) Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences) M Mengyuan Zhao (Chinese Academy of Sciences (CAS) Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences) Y Yingxu Fang (Chinese Academy of Sciences (CAS) Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences) B Bingxi Li (Chinese Academy of Sciences (CAS) Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences) J Jing Wang (Hunan Cancer Hospital Changsha China) Q Qiyao Chai (Chinese Academy of Sciences (CAS) Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences) C Cui Hua Liu (Chinese Academy of Sciences (CAS) Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences)

Abstract

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. Here, we identify mammalian cell entry 3C (Mce3C) as a pathogenic cell death regulator secreted by Mycobacterium tuberculosis (Mtb), which causes tuberculosis featured with lung inflammation and necrosis. Mce3C binds host cathepsin B (CTSB), a noncaspase protease acting as a lysosome-derived molecular determinant of cell death modalities, to inhibit its protease activity toward BH3-interacting domain death agonist (BID) and receptor-interacting protein kinase 1 (RIPK1), thereby preventing the production of proapoptotic truncated BID (tBID) while maintaining the abundance of pronecroptotic 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 in cell death modalities to promote infection and pathogenicity.

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Article Details

Journal Proceedings of the National Academy of Sciences

Volume / Issue Vol. 122, Issue 8

Published February 25, 2025

DOI 10.1073/pnas.2406715122

ISSN 0027-8424

Publisher National Academy of Sciences

Journal Info

Proceedings of the National Academy of Sciences

National Academy of Sciences

ISSN: 0027-8424 Life Sciences