Atomic mechanisms of full-length ASC-mediated inflammasome assembly

Dongmei Xue, Fengyun Ni, Sheng Liu, Huifang Yan, Zhenwei Luo, Gang Fu, Qinghua Wang () and Jianpeng Ma ()
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Dongmei Xue: Fudan University, Multiscale Research Institute for Complex Systems
Fengyun Ni: Fudan University, Multiscale Research Institute for Complex Systems
Sheng Liu: Fudan University, Multiscale Research Institute for Complex Systems
Huifang Yan: Fudan University, Multiscale Research Institute for Complex Systems
Zhenwei Luo: Fudan University, Multiscale Research Institute for Complex Systems
Gang Fu: UMass Chan Medical School, Biochemistry and Molecular Biotechnology Department
Qinghua Wang: Harcam Biomedicines, Center for Biomolecular Innovation
Jianpeng Ma: Fudan University, Multiscale Research Institute for Complex Systems

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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 ASCPYD and ASCCARD 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 ASCCARD 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.

Date: 2025
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DOI: 10.1038/s41467-025-65578-2

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