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

• Published in: Science (American Association for the Advancement of Science) Vol. 350; no. 6259; pp. 404 - 409
• Main Authors: Zhang, Liman, Chen, Shuobing, Ruan, Jianbin, Wu, Jiayi, Tong, Alexander B., Yin, Qian, Li, Yang, David, Liron, Lu, Alvin, Li Wang, Wei, Marks, Carolyn, Ouyang, Qi, Zhang, Xinzheng, Mao, Youdong, Wu, Hao
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 23.10.2015; The American Association for the Advancement of Science
• Subjects: Activation; Amino Acid Sequence; Animals; Apoptosis; Apoptosis Regulatory Proteins - chemistry; Assembly; Bacteria; Bacterial Proteins - chemistry; Binding; Biochemistry; Biophysics; Calcium-Binding Proteins - chemistry; CARD Signaling Adaptor Proteins - chemistry; Caspase 1 - chemistry; Cryoelectron Microscopy; Electron microscopy; Immunity, Innate; Inflammasomes - immunology; Ligands; Mice; Microorganisms; Molecular Sequence Data; Molecular structure; Neuronal Apoptosis-Inhibitory Protein - chemistry; Polymerization; Protein Interaction Maps; Protein Structure, Tertiary; Proteins
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aac5789

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 ∼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.