2. Academic Validation
  3. Mycobacterium tuberculosis modulates phosphorylation of host ATP6V1E1 to promote intracellular survival

Mycobacterium tuberculosis modulates phosphorylation of host ATP6V1E1 to promote intracellular survival

  • Nat Commun. 2026 Feb 6;17(1):2434. doi: 10.1038/s41467-026-69331-1.
Jianxia Chen # 1,  Fen Tang # 2,  Lianhua Qin # 3,  Weijun Fang 3,  Liru Guan 3,  Xiangyang Wu 1,  Haohao Li 1,  Yongjia Duan 3,  Fei Wang 3,  Cheng Peng 3,  Zhonghua Liu 3,  Jie Wang 3,  Xiaochen Huang 3,  Lin Wang 3 4,  Hua Yang 3 4,  Li Wang 5,  Wei Sha 3 5,  Xia Cai 6,  Liang-Dong Lyu 7 8,  Haipeng Liu 9 10,  Feng Liu 11,  Baoxue Ge 12 13 14,  Ruijuan Zheng 15 16
Affiliations

Affiliations

  • 1 Clinical and Translational Research Center, Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • 2 School of Medicine, Shanghai University, Shanghai, China.
  • 3 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, PR China.
  • 4 Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, PR China.
  • 5 Department of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • 6 Biosafety Level 3 Laboratory & Shanghai Medical College, Fudan University, Shanghai, PR China.
  • 7 Key Laboratory of Medical Molecular Virology of the Ministry of Education/Ministry of Health, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China. [email protected].
  • 8 Shanghai Clinical Research Center for Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Shanghai, China. [email protected].
  • 9 Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, PR China. [email protected].
  • 10 Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, PR China. [email protected].
  • 11 Department of Otolaryngology-Head and Neck Surgery, Otolaryngology Institute of Shanghai JiaoTong University, Shanghai Sixth People's Hospital Affiliated to JiaoTong University Medical School, Shanghai, China. [email protected].
  • 12 Clinical and Translational Research Center, Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. [email protected].
  • 13 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, PR China. [email protected].
  • 14 Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, PR China. [email protected].
  • 15 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, PR China. [email protected].
  • 16 Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, PR China. [email protected].
  • # Contributed equally.
PMID: 41651829 DOI: 10.1038/s41467-026-69331-1
Abstract

Intracellular pathogens such as Mycobacterium tuberculosis (Mtb) can promote their survival within infected cells by preventing lysosomal acidification. Here, we report that Mtb secretes a protein (Rv1184, or Acyltransferase Chp2) that inhibits lysosomal acidification by targeting the host vacuolar ATPase (V-ATPase). We show that phosphorylation of the V-ATPase E1 subunit (ATP6V1E1) at Tyr56/57 suppresses lysosomal acidification through inhibition of V-ATPase assembly. Further investigation reveals that tyrosine kinase BMX promotes phosphorylation of ATP6V1E1. Strikingly, Chp2 increases BMX-dependent phosphorylation of ATP6V1E1, apparently by directly binding ATP6V1E1 and facilitating its interaction with BMX. Furthermore, inhibition of BMX impairs Mtb growth within macrophages and in mice. Thus, our work reveals a mechanism for the regulation of lysosomal acidification and suggests lysosomal acidification modulation as a potential approach for host-directed therapy against Mtb.

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