ZNFX1 promotes AMPK-mediated autophagy against Mycobacterium tuberculosis by stabilizing Prkaa2 mRNA
Honglin Liu, … , Qian Wen, Li Ma
Honglin Liu, … , Qian Wen, Li Ma
Published November 28, 2023
Citation Information: JCI Insight. 2024;9(1):e171850. https://doi.org/10.1172/jci.insight.171850.
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Research Article Immunology Infectious disease

ZNFX1 promotes AMPK-mediated autophagy against Mycobacterium tuberculosis by stabilizing Prkaa2 mRNA

Abstract

Tuberculosis has the highest mortality rate worldwide for a chronic infectious disease caused by a single pathogen. RNA-binding proteins (RBPs) are involved in autophagy — a key defense mechanism against Mycobacterium tuberculosis (M. tuberculosis) infection — by modulating RNA stability and forming intricate regulatory networks. However, the functions of host RBPs during M. tuberculosis infection remain relatively unexplored. Zinc finger NFX1-type containing 1 (ZNFX1), a conserved RBP critically involved in immune deficiency diseases and mycobacterial infections, is significantly upregulated in M. tuberculosis–infected macrophages. Here, we aimed to explore the immunoregulatory functions of ZNFX1 during M. tuberculosis infection. We observed that Znfx1 knockout markedly compromised the multifaceted immune responses mediated by macrophages. This compromise resulted in reduced phagocytosis, suppressed macrophage activation, increased M. tuberculosis burden, progressive lung tissue injury, and chronic inflammation in M. tuberculosis–infected mice. Mechanistic investigations revealed that the absence of ZNFX1 inhibited autophagy, consequently mediating immune suppression. ZNFX1 critically maintained AMPK-regulated autophagic flux by stabilizing protein kinase AMP-activated catalytic subunit alpha 2 mRNA, which encodes a key catalytic α subunit of AMPK, through its zinc finger region. This process contributed to M. tuberculosis growth suppression. These findings reveal a function of ZNFX1 in establishing anti–M. tuberculosis immune responses, enhancing our understanding of the roles of RBPs in tuberculosis immunity and providing a promising approach to bolster antituberculosis immunotherapy.

Authors

Honglin Liu, Zhenyu Han, Liru Chen, Jing Zhang, Zhanqing Zhang, Yaoxin Chen, Feichang Liu, Ke Wang, Jieyu Liu, Na Sai, Xinying Zhou, Chaoying Zhou, Shengfeng Hu, Qian Wen, Li Ma

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Figure 2

In vivo immune response of Znfx1–/– mice infected with H37Rv.

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In vivo immune response of Znfx1–/– mice infected with H37Rv. (A) Schema...
(A) Schematic diagram of the time points of assays during the in vivo evaluation of Znfx1–/–-induced immune responses against M. tuberculosis infection. CK, cytokine. (B) In vivo M. tuberculosis load in the lung and spleen tissues of Znfx1–/– mice at 1 and 4 weeks after H37Rv infection (n = 5). (C) H&E staining of the lung and spleen tissues of Znfx1–/– mice. The splenic MGCs were quantified (n = 5, with 30 randomly selected fields of view for statistics). Yellow arrows indicate MGCs. (D) Measurement of NO production indicated as the concentration of NO2– in the lung and spleen tissues 1 week postinfection (n = 5). (E) Luminex multiplex assays of cytokine expression in the peripheral blood of mice 1 week after H37Rv infection (n = 5). (F) ELISA of cytokine expression in the lung and spleen of mice 1 week after H37Rv infection (n = 5). A 2-way ANOVA with Holm-Šídák post hoc test (B) or an unpaired 2-tailed t test was used (C–F) was used for statistical analysis. Data are presented as mean ± SD and are representative of at least 3 experiments with similar observations. **P < 0.01; ***P < 0.001; ****P < 0.0001.