Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 6, Pages 2052-2057Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1817221116
Keywords
NLRP6; inflammasome; innate immunity; cryo-EM; X-ray crystallography
Categories
Funding
- National Institutes of Health [A1124491, HD087988, R35GM122510]
- Harvard Digestive and Disease Center [HDDC P30 DK034854]
- Cancer Research Institute Irvington Postdoctoral Fellowship
- National Institute of General Medical Sciences from National Institutes of Health [P30 GM124165]
- National Institutes of Health Office of Research Infrastructure Programs High-End Instrumentation [S10OD021527]
- DOE Office of Science [DE-AC02-06CH11357]
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Inflammasomes are large protein complexes that trigger host defense in cells by activating inflammatory caspases for cytokine maturation and pyroptosis. NLRP6 is a sensor protein in the nucleotide-binding domain (NBD) and leucine-rich repeat (LRR)containing (NLR) inflammasome family that has been shown to play multiple roles in regulating inflammation and host defenses. Despite the significance of the NLRP6 inflammasome, little is known about the molecular mechanism behind its assembly and activation. Here we present cryo-EM and crystal structures of NLRP6 pyrin domain (PYD). We show that NLRP6 PYD alone is able to self-assemble into filamentous structures accompanied by large conformational changes and can recruit the ASC adaptor using PYD-PYD interactions. Using molecular dynamics simulations, we identify the surface that the NLRP6 PYD filament uses to recruit ASC PYD. We further find that full-length NLRP6 assembles in a concentration-dependent manner into wider filaments with a PYD core surrounded by the NBD and the LRR domain. These findings provide a structural understanding of inflammasome assembly by NLRP6 and other members of the NLR family.
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