Molecular mechanism for NLRP6 inflammasome assembly and activation

Shen, Chen; Lu, Alvin; Xie, Wen Jun; Ruan, Jianbin; Negro, Roberto; Egelman, Edward H.; Fu, Tian-Min; Wu, Hao

doi:10.1073/pnas.1817221116

Title: Molecular mechanism for NLRP6 inflammasome assembly and activation

Journal Article · Wed Jan 23 00:00:00 EST 2019 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1817221116· OSTI ID:1503698

Shen, Chen ^[1]; Lu, Alvin ^[1];

^[2]; Ruan, Jianbin ^[1]; Negro, Roberto ^[1]; Egelman, Edward H. ^[3]; Fu, Tian-Min ^[1]; Wu, Hao ^[1]

Harvard Medical School, Boston, MA (United States); Boston Children’s Hospital, MA (United States)
Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
Univ. of Virginia, Charlottesville, VA (United States)

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. Additionally, 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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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); Harvard Digestive and Disease Center; Cancer Research Institute; National Institute of General Medical Sciences (NIGMS); USDOE Office of Science (SC)

Grant/Contract Number:: Al124491; HD087988; R35GM122510; HDDC P30 DK034854; P30 GM124165; S10OD021527; AC02-06CH11357

OSTI ID:: 1503698

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, Issue 6; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 56 works

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59 BASIC BIOLOGICAL SCIENCES
NLRP6
inflammasome
innate immunity
cryo-EM
X-ray crystallography

Title: Molecular mechanism for NLRP6 inflammasome assembly and activation

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