{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:53:52Z","timestamp":1792785232458,"version":"4.5.0"},"reference-count":67,"publisher":"National Academy of Sciences","issue":"12","license":[{"start":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T00:00:00Z","timestamp":1742256000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015691","name":"HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases","doi-asserted-by":"publisher","award":["R21AI178133"],"award-info":[{"award-number":["R21AI178133"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015691","name":"HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases","doi-asserted-by":"publisher","award":["ROIAI155510"],"award-info":[{"award-number":["ROIAI155510"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000884","name":"Cancer Research Institute","doi-asserted-by":"publisher","award":["Fellowship"],"award-info":[{"award-number":["Fellowship"]}],"id":[{"id":"10.13039\/100000884","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Abby and Howard P. Milstein Program in Chemical Biology and Translational Medicine","award":["(no number)"],"award-info":[{"award-number":["(no number)"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,3,25]]},"abstract":"<jats:p>\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (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-\u03b2 (IFN-\u03b2) [L. Zhang et al.,\n                    <jats:italic>J. Exp. Med.<\/jats:italic>\n                    <jats:bold>18<\/jats:bold>\n                    , e20200887 (2021)]. Here, we identified a key downstream response to IFN-\u03b2 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\u2019s 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\u2019s 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2425309122","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T12:15:02Z","timestamp":1742300102000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["ACOD1-mediated lysosomal membrane permeabilization contributes to\n                    <i>Mycobacterium tuberculosis<\/i>\n                    \u2013induced macrophage death"],"prefix":"10.1073","volume":"122","author":[{"given":"Ziwei","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Ottavi","sequence":"additional","affiliation":[{"name":"Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy, University of North Carolina at Chapel Hill","place":["Chapel Hill"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob B.","family":"Geri","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Weill Cornell Medicine","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Perkowski","sequence":"additional","affiliation":[{"name":"Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy, University of North Carolina at Chapel Hill","place":["Chapel Hill"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuju","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Pfau","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruslana","family":"Bryk","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1049-5767","authenticated-orcid":false,"given":"Jeffrey","family":"Aub\u00e9","sequence":"additional","affiliation":[{"name":"Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy, University of North Carolina at Chapel Hill","place":["Chapel Hill"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Zimmerman","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health","place":["Nutley"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9470-5009","authenticated-orcid":false,"given":"V\u00e9ronique","family":"Dartois","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health","place":["Nutley"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7744-8896","authenticated-orcid":false,"given":"Carl","family":"Nathan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medicine","place":["New 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I. Machelart IRG1 controls host responses to restrict Mycobacterium tuberculosis infection. bioRxiv [Preprint] (2022). https:\/\/doi.org\/10.1101\/761551 (Accessed 26 September 2024).","DOI":"10.1101\/761551"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.05.009"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-022-00605-w"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abo2028"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2015.51"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep32247"},{"key":"e_1_3_4_67_2","unstructured":"L. Zhang C. F. Nathan Effects of type I IFN signaling on gene expression of Mycobacterium tuberculosis-infected bone marrow-derived macrophages (BMDMs). GEO. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE289356. 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