Mycobacterium tuberculosis (Mtb) primarily infects macrophages. In vitro without antibiotics, wild-type Mtb hastens death of the macrophages, but the processes leading to rapid cell death are not well understood. Our earlier work indicated that the death of Mtb-infected mouse macrophages in vitro is markedly exacerbated by induction of interferon-β (IFN-β) [L. Zhang et al., J. Exp. Med. 18 , e20200887 (2021)]. Here, we identified a key downstream response to IFN-β in the context of Mtb infection as the massive induction of cis-aconitate decarboxylase (ACOD1), not only in its canonical subcellular localization in mitochondria but also in the cytosol, where it bound to the lysosome-stabilizing protein HSP70. ACOD1’s product, itaconate, protected Mtb-infected macrophages. However, the contrasting and predominant effect of high-level ACOD1 expression was to act in a noncatalytic manner to promote HSP70’s degradation, leading to lysosomal membrane permeabilization (LMP). Mtb-induced macrophage death was markedly diminished by inhibitors of cysteine proteases, consistent with lysosome-mediated cell death. Neither ACOD1 inhibitors nor cysteine protease inhibitors are suitable for potential host-directed therapy (HDT) of tuberculosis. Instead, this work directs attention to how ACOD1 acts nonenzymatically to promote the degradation of HSP70.

中文翻译：

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ACOD1 介导的溶酶体膜通透性导致结核分枝杆菌诱导的巨噬细胞死亡


结核分枝杆菌 （Mtb） 主要感染巨噬细胞。在没有抗生素的体外，野生型 Mtb 会加速巨噬细胞的死亡，但导致细胞快速死亡的过程尚不清楚。我们早期的研究表明，干扰素-β （IFN-β） 的诱导显着加剧了 Mtb 感染的小鼠巨噬细胞在体外的死亡 [L. Zhang et al.， J. Exp. Med. 18 ， e20200887 （2021）]。在这里，我们确定了在 Mtb 感染背景下对 IFN-β 的关键下游反应，即顺乌头酸脱羧酶 （ACOD1） 的大量诱导，不仅在线粒体中的经典亚细胞定位，而且在胞质溶胶中，它与溶酶体稳定蛋白 HSP70 结合。ACOD1 的产物 itaconate 可保护 Mtb 感染的巨噬细胞。然而，高水平 ACOD1 表达的对比和主要作用是以非催化方式作用以促进 HSP70 的降解，导致溶酶体膜通透性 （LMP）。半胱氨酸蛋白酶抑制剂显着减少了 Mtb 诱导的巨噬细胞死亡，这与溶酶体介导的细胞死亡一致。ACOD1 抑制剂和半胱氨酸蛋白酶抑制剂都不适合用于结核病的潜在宿主定向治疗 （HDT）。相反，这项工作将注意力集中在 ACOD1 如何以非酶方式促进 HSP70 的降解。