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

• 成果类型: Article
• 署名作者: Lu, Zhe; Zhang, Yong; Zhong, Yanzhao; Qiang, Lihua; Ge, Pupu; Lei, Zehui; Zhao, Mengyuan; Fang, Yingxu; Li, Bingxi; Wang, Jing; Chai, Qiyao; Liu, Cui Hua
• 署名单位: Chinese Academy of Sciences; Institute of Microbiology, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12255
• DOI: 10.1073/pnas.2406715122
• 发表日期: 2025-02-25
• 关键词: mycobacterium-tuberculosis; t-lymphocytes; apoptosis; macrophage; necroptosis; resistance; cleavage; susceptibility; induction; PROGRAMS

摘要

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.