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Publication Abstract from PubMed

ASC (Apoptosis-associated Speck-like protein containing a CARD) is a key adaptor protein that assembles inflammasomes by linking sensors such as NLRP3 to effectors like Caspase-1 via its PYD and CARD Death Domains. Due to ASC's propensity to self-aggregate, most high-resolution structural studies focused on isolated PYD or CARD domains, leaving the atomic basis of full-length ASC assembly unknown. Here we determine atomic-resolution cryo-EM structures of PYD and CARD filaments from full-length ASC, revealing characteristic multitrack bundles composed of alternating ASC(PYD) and ASC(CARD) filaments that expose multiple interfaces for flexible assembly and efficient signaling. We further show that Caspase-1 filaments nucleate specifically from the B-end of ASC(CARD) filaments, and that the interdomain linker modulates bundle formation. The ASC isoform ASCb, with a four-residue linker, adopts a distinct architecture, correlating with reduced Caspase-1 activation efficiency. In ASC((-)/(-)) THP-1 cells, only wild-type ASC, not interface-disrupting mutants, restored ASC speck formation and Caspase-1 activation, underscoring the requirement for intact multitrack bundles. Cryo-electron tomography captures snapshots of higher-order inflammasome structures. These findings collectively define the structural and functional principles by which ASC organizes inflammasomes to amplify immune signaling.

Atomic mechanisms of full-length ASC-mediated inflammasome assembly.,Xue D, Ni F, Liu S, Yan H, Luo Z, Fu G, Wang Q, Ma J Nat Commun. 2025 Nov 26;16(1):10564. doi: 10.1038/s41467-025-65578-2. PMID:41298390^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.