Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization

被引：310

作者：

Zhang, Liman ^{[1
,2
]}

Chen, Shuobing ^{[3
,4
]}

Ruan, Jianbin ^{[1
,2
]}

Wu, Jiayi ^{[3
,4
]}

Tong, Alexander B. ^{[1
,2
]}

Yin, Qian ^{[1
,2
]}

Li, Yang ^{[1
,2
]}

David, Liron ^{[1
,2
]}

Lu, Alvin ^{[1
,2
]}

Wang, Wei Li ^{[4
,5
]}

Marks, Carolyn ^{[6
]}

Ouyang, Qi ^{[3
]}

Zhang, Xinzheng ^{[7
]}

Mao, Youdong ^{[3
,4
,5
]}

Wu, Hao ^{[1
,2
]}

机构：

[1] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[2] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA

[3] Peking Univ, Peking Tsinghua Joint Ctr Life, State Key Lab Artificial Microstruct & Mesoscop,S, Ctr Quantitat Biol,Acad Adv Interdisciplinary Stu, Beijing 100871, Peoples R China

[4] Dana Farber Canc Inst, Intel Parallel Comp Ctr Struct Biol, Dept Canc Immunol & Virol, Boston, MA 02215 USA

[5] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA

[6] Harvard Univ, Ctr Nanoscale Syst, Cambridge, MA 02138 USA

[7] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China

来源：

SCIENCE | 2015年 / 350卷 / 6259期

关键词：

CAUSES AUTOINFLAMMATION; BACTERIAL LIGANDS; CRYSTAL-STRUCTURE; NLRC4; CAUSES; APOPTOSOME; SECRETION; MUTATION; SIGNAL; RECOGNITION; CASPASE-1;

D O I：

10.1126/science.aac5789

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The NLR family apoptosis inhibitory proteins (NAIPs) bind conserved bacterial ligands, such as the bacterial rod protein PrgJ, and recruit NLR family CARD-containing protein 4 (NLRC4) as the inflammasome adapter to activate innate immunity. We found that the PrgJ-NAIP2-NLRC4 inflammasome is assembled into multisubunit disk-like structures through a unidirectional adenosine triphosphatase polymerization, primed with a single PrgJ-activated NAIP2 per disk. Cryo-electron microscopy (cryo-EM) reconstruction at subnanometer resolution revealed a similar to 90 degrees hinge rotation accompanying NLRC4 activation. Unlike in the related heptameric Apaf-1 apoptosome, in which each subunit needs to be conformationally activated by its ligand before assembly, a single PrgJ-activated NAIP2 initiates NLRC4 polymerization in a domino-like reaction to promote the disk assembly. These insights reveal the mechanism of signal amplification in NAIP-NLRC4 inflammasomes.

引用

页码：404 / 409

页数：6

共 30 条

[1] Calcium blocks formation of apoptosome by preventing nucleotide exchange in Apaf-1 [J].

Bao, Qing ;

Lu, Wenyun ;

Rabinowitz, Joshua D. ;

Shi, Yigong .

MOLECULAR CELL, 2007, 25 (02) :181-192

[2] The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response [J].

Baroja-Mazo, Alberto ;

Martin-Sanchez, Fatima ;

Gomez, Ana I. ;

Martinez, Carlos M. ;

Amores-Iniesta, Joaquin ;

Compan, Vincent ;

Barbera-Cremades, Maria ;

Yaguee, Jordi ;

Ruiz-Ortiz, Estibaliz ;

Anton, Jordi ;

Bujan, Segundo ;

Couillin, Isabelle ;

Brough, David ;

Arostegui, Juan I. ;

Pelegrin, Pablo .

NATURE IMMUNOLOGY, 2014, 15 (08) :738-+

[3] Prion-like Polymerization Underlies Signal Transduction in Antiviral Immune Defense and Inflammasome Activation [J].

Cai, Xin ;

Chen, Jueqi ;

Xu, Hui ;

Liu, Siqi ;

Jiang, Qiu-Xing ;

Halfmann, Randal ;

Chen, Zhijian J. .

CELL, 2014, 156 (06) :1207-1222

[4] An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome [J].

Canna, Scott W. ;

de Jesus, Adriana A. ;

Gounil, Sushanth ;

Brooks, Stephen R. ;

Marrero, Bernadette ;

Liu, Yin ;

DiMattia, Michael A. ;

Zaal, Kristien J. M. ;

Sanchez, Gina A. Montealegre ;

Kim, Hanna ;

Chapelle, Dawn ;

Plass, Nicole ;

Huang, Yan ;

Villarinol, Alejandro V. ;

Biancotto, Angelique ;

Fleisher, Thomas A. ;

Duncan, Joseph A. ;

O'Shea, John J. ;

Benseler, Susanne ;

Grom, Alexei ;

Deng, Zuoming ;

Laxer, Ronald M. ;

Goldbach-Mansky, Raphaela .

NATURE GENETICS, 2014, 46 (10) :1140-1146

[5] Birc1e is the gene within the Lgn1 locus associated with resistance to Legionella pneumophila [J].

Diez, E ;

Lee, SH ;

Gauthier, S ;

Yaraghi, Z ;

Tremblay, M ;

Vidal, S ;

Gros, P .

NATURE GENETICS, 2003, 33 (01) :55-60

[6] NLRC4-driven production of IL-1β discriminates between pathogenic and commensal bacteria and promotes host intestinal defense [J].

Franchi, Luigi ;

Kamada, Nobuhiko ;

Nakamura, Yuumi ;

Burberry, Aaron ;

Kuffa, Peter ;

Suzuki, Shiho ;

Shaw, Michael H. ;

Kim, Yun-Gi ;

Nunez, Gabriel .

NATURE IMMUNOLOGY, 2012, 13 (05) :449-U45

[7] The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation [J].

Franklin, Bernardo S. ;

Bossaller, Lukas ;

De Nardo, Dominic ;

Ratter, Jacqueline M. ;

Stutz, Andrea ;

Engels, Gudrun ;

Brenker, Christoph ;

Nordhoff, Mark ;

Mirandola, Sandra R. ;

Al-Amoudi, Ashraf ;

Mangan, Matthew S. ;

Zimmer, Sebastian ;

Monks, Brian G. ;

Fricke, Martin ;

Schmidt, Reinhold E. ;

Espevik, Terje ;

Jones, Bernadette ;

Jarnicki, Andrew G. ;

Hansbro, Philip M. ;

Busto, Patricia ;

Marshak-Rothstein, Ann ;

Hornemann, Simone ;

Aguzzi, Adriano ;

Kastenmueller, Wolfgang ;

Latz, Eicke .

NATURE IMMUNOLOGY, 2014, 15 (08) :727-+

[8] Simultaneous Targeting of Toll- and Nod-Like Receptors Induces Effective Tumor-Specific Immune Responses [J].

Garaude, Johan ;

Kent, Andrew ;

van Rooijen, Nico ;

Blander, J. Magarian .

SCIENCE TRANSLATIONAL MEDICINE, 2012, 4 (120)

[9] High-resolution genetic and physical map of the Lgnl interval in C57BL/6J implicates Naip2 or Naip5 in Legionella pneumophila pathogenesis [J].

Growney, JD ;

Dietrich, WF .

GENOME RESEARCH, 2000, 10 (08) :1158-1171

[10] Formation and Structure of a NAIP5-NLRC4 Inflammasome Induced by Direct Interactions with Conserved N- and C-terminal Regions of Flagellin [J].

Halff, Els F. ;

Diebolder, Christoph A. ;

Versteeg, Marian ;

Schouten, Arie ;

Brondijk, T. Harma C. ;

Huizinga, Eric G. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (46) :38460-38472

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