ACOD1-mediated lysosomal membrane permeabilization contributes to -induced macrophage death.

Journal:
Proceedings of the National Academy of Sciences of the United States of America, Volume: 122, Issue: 12
Published:
March 25, 2025
PMID:
40100622
Authors:
Ziwei Yang Z, Li Zhang L, Samantha Ottavi S, Jacob B Geri JB, Andrew Perkowski A, Xiuju Jiang X, Daniel Pfau D, Ruslana Bryk R, Jeffrey Aubé J, Matthew Zimmerman M, Véronique Dartois V, Carl Nathan C
Abstract:

(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., , 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.


Courtesy of the U.S. National Library of Medicine