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Ruan, Jianbin

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Ruan

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Jianbin

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Ruan, Jianbin
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    Plasticity in PYD assembly revealed by cryo-EM structure of the PYD filament of AIM2
    (2015) Lu, Alvin Z.; Li, Yang; Yin, Qian; Ruan, Jianbin; Yu, Xiong; Egelman, Edward; Wu, Hao
    Absent in melanoma 2 (AIM2) is an essential cytosolic double-stranded DNA receptor that assembles with the adaptor, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1 to form the AIM2 inflammasome, which leads to proteolytic maturation of cytokines and pyroptotic cell death. AIM2 contains an N-terminal Pyrin domain (PYD) that interacts with ASC through PYD/PYD interactions and nucleates ASCPYD filament formation. To elucidate the molecular basis of AIM2-induced ASCPYD polymerization, we generated AIM2PYD filaments fused to green fluorescent protein (GFP) and determined its cryo-electron microscopic (cryo-EM) structure. The map showed distinct definition of helices, allowing fitting of the crystal structure. Surprisingly, the GFP-AIM2PYD filament is a 1-start helix with helical parameters distinct from those of the 3-start ASCPYD filament. However, despite the apparent symmetry difference, helical net and detailed interface analyses reveal minimal changes in subunit packing. GFP-AIM2PYD nucleated ASCPYD filament formation in comparable efficiency as untagged AIM2PYD, suggesting assembly plasticity in both AIM2PYD and ASCPYD. The DNA-binding domain of AIM2 is able to form AIM2/DNA filaments, within which the AIM2PYD is brought into proximity to template ASCPYD filament assembly. Because ASC is able to interact with many PYD-containing receptors for the formation of inflammasomes, the observed structural plasticity may be critically important for this versatility in the PYD/PYD interactions.
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    A single domain antibody fragment that recognizes the adaptor ASC defines the role of ASC domains in inflammasome assembly
    (The Rockefeller University Press, 2016) Schmidt, Florian I.; Lu, Alvin; Chen, Jeff W.; Ruan, Jianbin; Tang, Catherine; Wu, Hao; Ploegh, Hidde L.
    Myeloid cells assemble inflammasomes in response to infection or cell damage; cytosolic sensors activate pro–caspase-1, indirectly for the most part, via the adaptors ASC and NLRC4. This leads to secretion of proinflammatory cytokines and pyroptosis. To explore complex formation under physiological conditions, we generated an alpaca single domain antibody, VHHASC, which specifically recognizes the CARD of human ASC via its type II interface. VHHASC not only impairs ASCCARD interactions in vitro, but also inhibits inflammasome activation in response to NLRP3, AIM2, and NAIP triggers when expressed in living cells, highlighting a role of ASC in all three types of inflammasomes. VHHASC leaves the Pyrin domain of ASC functional and stabilizes a filamentous intermediate of inflammasome activation. Incorporation of VHHASC-EGFP into these structures allowed the visualization of endogenous ASCPYD filaments for the first time. These data revealed that cross-linking of ASCPYD filaments via ASCCARD mediates the assembly of ASC foci.