Structural highlights
Function
CASP1_HUMAN Thiol protease that cleaves IL-1 beta between an Asp and an Ala, releasing the mature cytokine which is involved in a variety of inflammatory processes. Important for defense against pathogens. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Can also promote apoptosis.[1] [2]
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.
References
- ↑ Alnemri ES, Fernandes-Alnemri T, Litwack G. Cloning and expression of four novel isoforms of human interleukin-1 beta converting enzyme with different apoptotic activities. J Biol Chem. 1995 Mar 3;270(9):4312-7. PMID:7876192
- ↑ Feng Q, Li P, Leung PC, Auersperg N. Caspase-1zeta, a new splice variant of the caspase-1 gene. Genomics. 2004 Sep;84(3):587-91. PMID:15498465 doi:http://dx.doi.org/S0888-7543(04)00161-2
- ↑ Xue D, Ni F, Liu S, Yan H, Luo Z, Fu G, Wang Q, Ma J. Atomic mechanisms of full-length ASC-mediated inflammasome assembly. Nat Commun. 2025 Nov 26;16(1):10564. PMID:41298390 doi:10.1038/s41467-025-65578-2
