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FEBS Lett . 2020 Jun 16

Crystal structure of the human NLRP9 pyrin domain suggests a distinct mode of inflammasome assembly

Branko Cirovic, L Charlotte J de Bree, Laszlo Groh, Bas A Blok, Joyce Chan, Walter J F M van der Velden, M E J Bremmers, Reinout van Crevel, Kristian Händler, Simone Picelli, Jonas Schulte-Schrepping, Kathrin Klee, Marije Oosting, Valerie A C M Koeken, Jakko van Ingen, Yang Li, Christine S Benn, Joachim L Schultze, Leo A B Joosten, Nigel Curtis, Mihai G Netea, Andreas Schlitzer, Maria Elisa Mancuso, Johannes Oldenburg, Lisa Boggio, Gili Kenet, Anthony Chan, Carmen Altisent, Wilfried Seifert, Elena Santagostino, Michael Marleaux, Kanchan Anand, Eicke Latz, Matthias Geyer

Inflammasomes are cytosolic multimeric signaling complexes of the innate immune system that induce activation of caspases. The NOD-like receptor NLRP9 recruits the adaptor protein ASC to form an ASC-dependent inflammasome to limit rotaviral replication in intestinal epithelial cells, but only little is known about the molecular mechanisms regulating and driving its assembly. Here, we present the crystal structure of the human NLRP9 pyrin domain (PYD). We show that NLRP9PYD is not able to self-polymerize nor to nucleate ASC specks in HEK293T cells. A comparison with filament-forming PYDs revealed that NLRP9PYD adopts a conformation compatible with filament formation, but several charge inversions of interfacing residues might cause repulsive effects that prohibit self-oligomerization. These results propose that inflammasome assembly of NLRP9 might differ largely from what we know of other inflammasomes.

PMID: 32542665