Unified Polymerization Mechanism for the Assembly of ASC-dependent Inflammasomes

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2014 Mar 18

PMID 24630722

Citations 684

Authors

Alvin Lu

Venkat Giri Magupalli

Jianbin Ruan

Qian Yin

Maninjay K Atianand

Matthijn R Vos

Gunnar F Schroder

Katherine A Fitzgerald

Hao Wu

Edward H Egelman

Affiliations

Soon will be listed here.

Abstract

Inflammasomes elicit host defense inside cells by activating caspase-1 for cytokine maturation and cell death. AIM2 and NLRP3 are representative sensor proteins in two major families of inflammasomes. The adaptor protein ASC bridges the sensor proteins and caspase-1 to form ternary inflammasome complexes, achieved through pyrin domain (PYD) interactions between sensors and ASC and through caspase activation and recruitment domain (CARD) interactions between ASC and caspase-1. We found that PYD and CARD both form filaments. Activated AIM2 and NLRP3 nucleate PYD filaments of ASC, which, in turn, cluster the CARD of ASC. ASC thus nucleates CARD filaments of caspase-1, leading to proximity-induced activation. Endogenous NLRP3 inflammasome is also filamentous. The cryoelectron microscopy structure of ASC(PYD) filament at near-atomic resolution provides a template for homo- and hetero-PYD/PYD associations, as confirmed by structure-guided mutagenesis. We propose that ASC-dependent inflammasomes in both families share a unified assembly mechanism that involves two successive steps of nucleation-induced polymerization. PAPERFLICK:

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