Mycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine

Cheng Peng, Yuanna Cheng, Mingtong Ma, Qiu Chen, Yongjia Duan, Shanshan Liu, Hongyu Cheng, Hua Yang, Jingping Huang, Wenyi Bu, Chenyue Shi, Xiangyang Wu, Jianxia Chen, Ruijuan Zheng, Zhonghua Liu, Zhe Ji, Jie Wang, Xiaochen Huang, Peng Wang, Wei Sha, Baoxue Ge () and Lin Wang ()
Additional contact information
Cheng Peng: Tongji University School of Medicine
Yuanna Cheng: Tongji University School of Medicine
Mingtong Ma: Tongji University School of Medicine
Qiu Chen: Tongji University School of Medicine
Yongjia Duan: Tongji University School of Medicine
Shanshan Liu: Tongji University School of Medicine
Hongyu Cheng: Tongji University School of Medicine
Hua Yang: Tongji University School of Medicine
Jingping Huang: Tongji University School of Medicine
Wenyi Bu: Tongji University School of Medicine
Chenyue Shi: Tongji University School of Medicine
Xiangyang Wu: Tongji University School of Medicine
Jianxia Chen: Tongji University School of Medicine
Ruijuan Zheng: Tongji University School of Medicine
Zhonghua Liu: Tongji University School of Medicine
Zhe Ji: Tongji University School of Medicine
Jie Wang: Tongji University School of Medicine
Xiaochen Huang: Tongji University School of Medicine
Peng Wang: Tongji University School of Medicine
Wei Sha: Tongji University School of Medicine
Baoxue Ge: Tongji University School of Medicine
Lin Wang: Tongji University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Antimicrobial peptides (AMPs), ancient scavengers of bacteria, are very poorly induced in macrophages infected by Mycobacterium tuberculosis (M. tuberculosis), but the underlying mechanism remains unknown. Here, we report that L-alanine interacts with PRSS1 and unfreezes the inhibitory effect of PRSS1 on the activation of NF-κB pathway to induce the expression of AMPs, but mycobacterial alanine dehydrogenase (Ald) Rv2780 hydrolyzes L-alanine and reduces the level of L-alanine in macrophages, thereby suppressing the expression of AMPs to facilitate survival of mycobacteria. Mechanistically, PRSS1 associates with TAK1 and disruptes the formation of TAK1/TAB1 complex to inhibit TAK1-mediated activation of NF-κB pathway, but interaction of L-alanine with PRSS1, disables PRSS1-mediated impairment on TAK1/TAB1 complex formation, thereby triggering the activation of NF-κB pathway to induce expression of AMPs. Moreover, deletion of antimicrobial peptide gene β-defensin 4 (Defb4) impairs the virulence by Rv2780 during infection in mice. Both L-alanine and the Rv2780 inhibitor, GWP-042, exhibits excellent inhibitory activity against M. tuberculosis infection in vivo. Our findings identify a previously unrecognized mechanism that M. tuberculosis uses its own alanine dehydrogenase to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.

Date: 2024
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DOI: 10.1038/s41467-024-48588-4

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