ACOD1-mediated lysosomal membrane permeabilization contributes to <i>Mycobacterium tuberculosis</i>-induced macrophage death.

ABSTRACT: 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.

SUBMITTER: Yang Z 

PROVIDER: S-EPMC11962489 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature