Inflammasomes are supramolecular signaling complexes that activate a subset of caspases known as inflammatory caspases such as caspase-1. Upon stimulation by microbial and damage-associated signals, inflammasomes assemble to elicit the first line of host defense by proteolytic maturation of cytokines IL-1? and IL-18, and by induction of pyroptotic cell death. Assembly of an inflammasome requires activation of an upstream sensor, a downstream effector, and in most cases an adaptor molecule such as apoptosis-associate speck-like protein containing a caspase recruitment domain (ASC). Depending on whether ASC is required, inflammasomes can be categorized into ASC-dependent and ASC-independent inflammasomes. Despite the biological importance of inflammasomes in innate immunity, no structural and mechanistic information is available. In this application, we propose structural, biochemical, biophysical and cell biological studies on AIM2, NLRP3 and NAIP inflammasomes, which are representative members of ASC-dependent and ASC-independent inflammasomes. The key structural scaffolds for the assembly of these inflammasomes are composed of filaments of Pyrin domains (PYD) and caspase recruitment domains (CARD), and polymerized disk-like structures by nucleotide-binding domains (NBD). Inflammasomes have been implicated in many human diseases. Most notably, failure to curb the activity of inflammasomes is linked to autoinflammatory conditions such as familial Mediterranean fever and NLRP3-associated periodic syndromes including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous and articular syndrome?neonatal onset multisystem inflammatory disease. As predisposing factors, inflammasome component proteins have been associated with many inflammatory diseases such as psoriasis, lupus, and inflammatory bowel diseases such as ulcerative colitis and Crohn's diseases.
Engagement of the inflammasome pathways in appropriate physiological contexts is important for pathogen recognition and initiates protective immune responses. However, the complexity of this pathway also renders itself susceptible to interruption and dysregulation, leading to its association with many human diseases, such as autoinflammatory diseases, and autoimmune diseases. Understanding this pathway at the molecular level would contribute to both health and disease.
|Evavold, Charles L; Ruan, Jianbin; Tan, Yunhao et al. (2018) The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion from Living Macrophages. Immunity 48:35-44.e6|
|Li, Yang; Fu, Tian-Min; Lu, Alvin et al. (2018) Cryo-EM structures of ASC and NLRC4 CARD filaments reveal a unified mechanism of nucleation and activation of caspase-1. Proc Natl Acad Sci U S A 115:10845-10852|
|Ruan, Jianbin; Xia, Shiyu; Liu, Xing et al. (2018) Cryo-EM structure of the gasdermin A3 membrane pore. Nature 557:62-67|
|Wang, Huaimin; Feng, Zhaoqianqi; Lu, Alvin et al. (2017) Instant Hydrogelation Inspired by Inflammasomes. Angew Chem Int Ed Engl 56:7579-7583|
|Wang, Li; Qiao, Qi; Wu, Hao (2017) Understanding CARD Tricks in Apoptosomes. Structure 25:575-577|
|Lu, Alvin; Li, Yang; Schmidt, Florian I et al. (2016) Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism. Nat Struct Mol Biol 23:416-25|
|Schmidt, Florian I; Lu, Alvin; Chen, Jeff W et al. (2016) A single domain antibody fragment that recognizes the adaptor ASC defines the role of ASC domains in inflammasome assembly. J Exp Med 213:771-90|
|Wu, Hao; Fuxreiter, Monika (2016) The Structure and Dynamics of Higher-Order Assemblies: Amyloids, Signalosomes, and Granules. Cell 165:1055-1066|
|Liu, Xing; Zhang, Zhibin; Ruan, Jianbin et al. (2016) Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535:153-8|
|Fu, Tian-Min; Li, Yang; Lu, Alvin et al. (2016) Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling Complex. Mol Cell 64:236-250|
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