BioChem - DOS

Mycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine

Nature communications

Peng, Cheng; Cheng, Yuanna; Ma, Mingtong; Chen, Qiu; Duan, Yongjia; Liu, Shanshan; Cheng, Hongyu; Yang, Hua; Huang, Jingping; Bu, Wenyi; Shi, Chenyue; Wu, Xiangyang; Chen, Jianxia; Zheng, Ruijuan; Liu, Zhonghua; Ji, Zhe; Wang, Jie; Huang, Xiaochen; Wang, Peng; Sha, Wei; Ge, Baoxue; Wang, Lin

<P><B>Abstract</B><P>Antimicrobial peptides (AMPs), ancient scavengers of bacteria, are very poorly induced in macrophages infected by <I>Mycobacterium tuberculosis</I> (<I>M. tuberculosis</I>), 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-&kappa;B 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-&kappa;B pathway, but interaction of L-alanine with PRSS1, disables PRSS1-mediated impairment on TAK1/TAB1 complex formation, thereby triggering the activation of NF-&kappa;B pathway to induce expression of AMPs. Moreover, deletion of antimicrobial peptide gene <I>&beta;-defensin 4</I> (<I>Defb4</I>) impairs the virulence by Rv2780 during infection in mice. Both L-alanine and the Rv2780 inhibitor, GWP-042, exhibits excellent inhibitory activity against <I>M. tuberculosis</I> infection in vivo. Our findings identify a previously unrecognized mechanism that <I>M. tuberculosis</I> uses its own alanine dehydrogenase to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target <I>M. tuberculosis</I>.</P></P>

2024

Springer Science and Business Media LLC

2041-1723

15

1

pp.4216

10.1038/s41467-024-48588-4

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