Structural Basis for Distinct Inflammasome Complex Assembly by Human NLRP1 and CARD8

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Jan 9

PMID 33420028

Citations 36

Authors

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

Bin Wu

Affiliations

Soon will be listed here.

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 (FIIND-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIIND-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIIND. 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-FIIND 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.

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