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-Structure paper
タイトル | Mechanism of filament formation in UPA-promoted CARD8 and NLRP1 inflammasomes. |
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ジャーナル・号・ページ | Nat Commun, Vol. 12, Issue 1, Page 189, Year 2021 |
掲載日 | 2021年1月8日 |
著者 | L Robert Hollingsworth / Liron David / Yang Li / Andrew R Griswold / Jianbin Ruan / Humayun Sharif / Pietro Fontana / Elizabeth L Orth-He / Tian-Min Fu / Daniel A Bachovchin / Hao Wu / |
PubMed 要旨 | NLRP1 and CARD8 are related cytosolic sensors that upon activation form supramolecular signalling complexes known as canonical inflammasomes, resulting in caspase-1 activation, cytokine maturation ...NLRP1 and CARD8 are related cytosolic sensors that upon activation form supramolecular signalling complexes known as canonical inflammasomes, resulting in caspase-1 activation, cytokine maturation and/or pyroptotic cell death. NLRP1 and CARD8 use their C-terminal (CT) fragments containing a caspase recruitment domain (CARD) and the UPA (conserved in UNC5, PIDD, and ankyrins) subdomain for self-oligomerization, which in turn form the platform to recruit the inflammasome adaptor ASC (apoptosis-associated speck-like protein containing a CARD) or caspase-1, respectively. Here, we report cryo-EM structures of NLRP1-CT and CARD8-CT assemblies, in which the respective CARDs form central helical filaments that are promoted by oligomerized, but flexibly linked, UPAs surrounding the filaments. Through biochemical and cellular approaches, we demonstrate that the UPA itself reduces the threshold needed for NLRP1-CT and CARD8-CT filament formation and signalling. Structural analyses provide insights on the mode of ASC recruitment by NLRP1-CT and the contrasting direct recruitment of caspase-1 by CARD8-CT. We also discover that subunits in the central NLRP1 filament dimerize with additional exterior CARDs, which roughly doubles its thickness and is unique among all known CARD filaments. Finally, we engineer and determine the structure of an ASC-caspase-1 octamer, which suggests that ASC uses opposing surfaces for NLRP1, versus caspase-1, recruitment. Together these structures capture the architecture and specificity of the active NLRP1 and CARD8 inflammasomes in addition to key heteromeric CARD-CARD interactions governing inflammasome signalling. |
リンク | Nat Commun / PubMed:33420033 / PubMed Central |
手法 | EM (らせん対称) / EM (単粒子) |
解像度 | 3.54 - 5.0 Å |
構造データ | EMDB-22219, PDB-6xkj: EMDB-22220, PDB-6xkk: EMDB-22233: Cryo-EM structure of ASC-Caspase1 Octamer |
由来 |
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キーワード | IMMUNE SYSTEM (免疫系) / Filament / inflammasome (インフラマソーム) / signaling / UPA / FIIND / CARD / NLRP1 / ASC / Apoptosis-associated speck-like protein containing a CARD / PYCARD / caspase-1 (カスパーゼ-1) / cryo-EM (低温電子顕微鏡法) / helical filament / octamer (オリゴマー) |