{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T14:52:33Z","timestamp":1781103153091,"version":"3.54.1"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"19","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,5,12]]},"abstract":"<jats:p>\n                    Inflammasome activation triggers caspase-1-dependent maturation of pro-interleukin-1\u03b2 (pro-IL-1\u03b2) in an apoptosis-associated speck-like protein containing a CARD (ASC)-dependent manner, yet the mechanism by which pro-IL-1\u03b2 is physically recruited to the ASC signaling platform has remained undefined. Here, we identify the ASC linker domain (ASC\n                    <jats:sup>LD<\/jats:sup>\n                    ) as a noncanonical protein-interaction interface, that can directly recruits pro-IL-1\u03b2 onto the ASC speck. Using a live-cell NanoBRET assay, confocal imaging, and pulldown analysis, we show that ASC directly engages pro-IL-1\u03b2 and that this interaction requires a discrete set of charged residues in the IL-1\u03b2 mature domain region, forming an ASC-docking surface. Mutagenesis guided by the IL-1\u03b2 structure confirmed that this interaction is essential for caspase-1-dependent IL-1\u03b2 maturation but dispensable for pyroptosis. Domain mapping revealed that ASC\n                    <jats:sup>LD<\/jats:sup>\n                    , rather than its N-terminal Pyrin domain (PYD) or C-terminal caspase recruitment domain (CARD), mediates pro-IL-1\u03b2 recruitment. Using an in-house custom antibody against ASC\n                    <jats:sup>LD<\/jats:sup>\n                    , we show that this region remains exposed within endogenous ASC specks in macrophages. Mutational disruption of ASC\n                    <jats:sup>LD<\/jats:sup>\n                    selectively impaired IL-1\u03b2 processing in THP-1 cells Mutations disruption data was obtained from THP-1 cells without affecting ASC speck formation or pyroptosis. A cell-penetrating peptide derived from ASC\n                    <jats:sup>LD<\/jats:sup>\n                    selectively blocked pro-IL-1\u03b2 docking while preserving speck assembly. In 2 mouse models of peritonitis, the blocking peptide uncoupled cytokine maturation from pyroptosis and significantly reduced IL-1\u03b2-driven inflammation. Thus, our findings uncover ASC\n                    <jats:sup>LD<\/jats:sup>\n                    as a critical docking interface that positions pro-IL-1\u03b2 for efficient caspase-1 processing, which adds a mechanistic checkpoint within inflammasomes to license cytokine maturation independently of pyroptotic death. We propose that ASC\n                    <jats:sup>LD<\/jats:sup>\n                    may be a therapeutically tractable node for selective modulation of IL-1\u03b2-driven inflammasomopathies.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2537563123","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T09:47:13Z","timestamp":1778579233000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Inflammasome adaptor protein ASC is a mechanistic checkpoint in IL-1\u03b2 maturation"],"prefix":"10.1073","volume":"123","author":[{"given":"Giti","family":"Saha","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Mechanistic Cell Signaling, Lindsley F. Kimball Research Institute, New York Blood Center","place":["Rye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratibha","family":"Anchi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Mechanistic Cell Signaling, Lindsley F. Kimball Research Institute, New York Blood Center","place":["Rye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Mechanistic Cell Signaling, Lindsley F. Kimball Research Institute, New York Blood Center","place":["Rye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa","family":"Biondo","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Regenerative Research, Lindsley F. Kimball Research Institute, New York Blood Center","place":["Rye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadie","family":"Meyer","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Mechanistic Cell Signaling, Lindsley F. Kimball Research Institute, New York Blood Center","place":["Rye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinata","family":"Kondragunta","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Mechanistic Cell Signaling, Lindsley F. Kimball Research Institute, New York Blood Center","place":["Rye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0063-1764","authenticated-orcid":false,"given":"Larry L.","family":"Luchsinger","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Regenerative Research, Lindsley F. Kimball Research Institute, New York Blood Center","place":["Rye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismail","family":"Syed","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Deaconess Medical Center and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Humayun","family":"Sharif","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Medicine and Health Sciences, Khalifa University","place":["Abu Dhabi, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7281-8579","authenticated-orcid":false,"given":"Hao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School","place":["Boston"]},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkat","family":"Giri Magupalli","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Mechanistic Cell Signaling, Lindsley F. 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