| Title | Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome |
| Authors | Sharif, Humayun Wang, Li Wang, Wei Li Magupalli, Venkat Giri Andreeva, Liudmila Qiao, Qi Hauenstein, Arthur V. Wu, Zhaolong Nunez, Gabriel Mao, Youdong Wu, Hao |
| Affiliation | Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA Peking Univ, Sch Phys, State Key Lab Artificial Microstruct & Mesoscop P, Beijing, Peoples R China Peking Univ, Ctr Quantitat Biol, Beijing, Peoples R China Dana Farber Canc Inst, Intel Parallel Comp Ctr Struct Biol, Boston, MA 02115 USA Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA Harvard Med Sch, Dept Microbiol, Boston, MA 02115 USA Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI USA |
| Issue Date | 2019 |
| Publisher | NATURE |
| Abstract | The NLRP3 inflammasome can be activated by stimuli that include nigericin, uric acid crystals, amyloid-beta fibrils and extracellnlar ATP. The mitotic kinase NEK7 licenses the assembly and activation of the NLRP3 inflammasome in interphase. Here we report a cryo-electron microscopy structure of inactive human NLRP3 in complex with NEK7, at a resolution of 3.8 angstrom. The earring-shaped NLRP3 consists of curved leucine -rich-repeat and globular NACHT domains, and the C-terminal lobe of NEK7 nestles against both NLRP3 domains. Structural recognition between NLRP3 and NEK7 is confirmed by mutagenesis both in vitro and in cells. Modelling of an active NLRP3-NEK7 conformation based on the NLRC4 inflammasome predicts an additional contact between an NLRP3-bound NEK7 and a neighbouring NLRP3. Mutations to this interface abolish the ability of NEK7 or NLRP3 to rescue NLRP3 activation in NEK7-knockout or NLRP3-knockout cells. These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. |
| URI | http://hdl.handle.net/20.500.11897/547404 |
| ISSN | 0028-0836 |
| DOI | 10.1038/s41586-019-1295-z |
| Indexed | SCI(E) EI |
| Appears in Collections: | 物理学院 人工微结构和介观物理国家重点实验室 生命科学学院 |
