ACOD1-mediated lysosomal membrane permeabilization contributes to Mycobacterium tuberculosis-induced macrophage death

• 成果类型: Article
• 署名作者: Yang, Ziwei; Zhang, Li; Ottavi, Samantha; Geri, Jacob B.; Perkowski, Andrew; Jiang, Xiuju; Pfau, Daniel; Bryk, Ruslana; Aube, Jeffrey; Zimmerman, Matthew; Dartois, Veronique; Nathan, Carl
• 署名单位: Cornell University; Weill Cornell Medicine; Southern University of Science & Technology; University of North Carolina; University of North Carolina Chapel Hill; Cornell University; Weill Cornell Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8997
• DOI: 10.1073/pnas.2425309122
• 发表日期: 2025-03-25
• 关键词: calpain inhibitor; cytochrome-c; protein; apoptosis; release; damage; cells; tfeb

摘要

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-f3 (IFN-f3) [L. Zhang et al.,J. Exp. Med. 18, e20200887 (2021)]. Here, we identified a key downstream response to IFN-f3 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.