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

Liman Zhang; Shuobing Chen; Jianbin Ruan; Jiayi Wu; Alexander B. Tong; Qian Yin; Yang Li; Liron David; Alvin Lu; Wei Li Wang; Carolyn Marks; Qi Ouyang; Xinzheng Zhang; Youdong Mao; Hao Wu

doi:10.1126/science.aac5789

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

Liman Zhang, Shuobing Chen, Jianbin Ruan, Jiayi Wu, Alexander B. Tong, Qian Yin, Yang Li, Liron David, Alvin Lu, Wei Li Wang, Carolyn Marks, Qi Ouyang, Xinzheng Zhang, Youdong Mao, Hao Wu

Research output: Contribution to journal › Article › peer-review

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Abstract

The NLR family apoptosis inhibitory proteins (NAIPs) bind conserved bacterial ligands, such as the bacterial rod protein Prg J, 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 ∼90° 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.

Original language	English (US)
Pages (from-to)	404-409
Number of pages	6
Journal	Science
Volume	350
Issue number	6259
DOIs	https://doi.org/10.1126/science.aac5789
State	Published - Oct 23 2015
Externally published	Yes

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title = "Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization",

abstract = "The NLR family apoptosis inhibitory proteins (NAIPs) bind conserved bacterial ligands, such as the bacterial rod protein Prg J, 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 ∼90° 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.",

author = "Liman Zhang and Shuobing Chen and Jianbin Ruan and Jiayi Wu and Tong, {Alexander B.} and Qian Yin and Yang Li and Liron David and Alvin Lu and Wang, {Wei Li} and Carolyn Marks and Qi Ouyang and Xinzheng Zhang and Youdong Mao and Hao Wu",

year = "2015",

month = oct,

day = "23",

doi = "10.1126/science.aac5789",

language = "English (US)",

volume = "350",

pages = "404--409",

journal = "Science",

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T1 - Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization

AU - Zhang, Liman

AU - Chen, Shuobing

AU - Ruan, Jianbin

AU - Wu, Jiayi

AU - Tong, Alexander B.

AU - Yin, Qian

AU - Li, Yang

AU - David, Liron

AU - Lu, Alvin

AU - Wang, Wei Li

AU - Marks, Carolyn

AU - Ouyang, Qi

AU - Zhang, Xinzheng

AU - Mao, Youdong

AU - Wu, Hao

PY - 2015/10/23

Y1 - 2015/10/23

N2 - The NLR family apoptosis inhibitory proteins (NAIPs) bind conserved bacterial ligands, such as the bacterial rod protein Prg J, 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 ∼90° 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.

AB - The NLR family apoptosis inhibitory proteins (NAIPs) bind conserved bacterial ligands, such as the bacterial rod protein Prg J, 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 ∼90° 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.

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JO - Science

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

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