Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

Qin Gong, Kim Robinson, Chenrui Xu, Phuong Thao Huynh, Kelvin Han Chung Chong, Eddie Yong Jun Tan, Jiawen Zhang, Zhao Zhi Boo, Daniel Eng Thiam Teo, Kenneth Lay, Yaming Zhang, John Soon Yew Lim, Wah Ing Goh, Graham Wright, Franklin L. Zhong (), Bruno Reversade () and Bin Wu ()
Additional contact information
Qin Gong: Nanyang Technological University
Kim Robinson: Agency of Science Technology and Research (A*STAR)
Chenrui Xu: Nanyang Technological University
Phuong Thao Huynh: Nanyang Technological University
Kelvin Han Chung Chong: Nanyang Technological University
Eddie Yong Jun Tan: Nanyang Technological University
Jiawen Zhang: Nanyang Technological University
Zhao Zhi Boo: Nanyang Technological University
Daniel Eng Thiam Teo: Agency of Science Technology and Research (A*STAR)
Kenneth Lay: Agency of Science Technology and Research (A*STAR)
Yaming Zhang: Nanyang Technological University
John Soon Yew Lim: Agency of Science Technology and Research (A*STAR)
Wah Ing Goh: Agency of Science Technology and Research (A*STAR)
Graham Wright: Agency of Science Technology and Research (A*STAR)
Franklin L. Zhong: Agency of Science Technology and Research (A*STAR)
Bruno Reversade: Agency of Science Technology and Research (A*STAR)
Bin Wu: Nanyang Technological University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related sensor proteins NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, their mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIINDUPA. Biochemically, self-assembled NLRP1-CARD filaments are sufficient to drive ASC speck formation in cultured human cells—a process that is greatly enhanced by NLRP1-FIINDUPA which forms oligomers in vitro. The cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments, solved here at 3.7 Å, uncover unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide structural insight into the mechanisms of activation for human NLRP1 and CARD8 and reveal how highly specific signaling can be achieved by heterotypic CARD interactions within the inflammasome complexes.

Date: 2021
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DOI: 10.1038/s41467-020-20319-5

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