Innate immune signaling requires careful coordination such that the adaptive immune system can be tailored to eradicate an offending pathogen. Too much signaling can result in autoinflammatory disease while too little signaling can result in immunodeficiency. Interestingly, immunodeficiency is often complicated by hyper- inflammatory states, and the maintenance of this inflammatory balance is particularly important in the intracellular pathogen recognition signaling system driven by the NOD2:RIPK2 complex. Loss-of-function polymorphisms in NOD2 cause decreased signaling in response to bacterial infection and predispose to Crohn?s disease, a disorder characterized by acute and chronic inflammation of the gastrointestinal tract. In contrast, gain-of-function NOD2 mutations, which cause increased signaling in response to bacterial infection, cause Early Onset Sarcoidosis, an inflammatory disorder characterized by uveitis and granulomatous inflammation in the mediastinum. Even WT NOD2 and WT RIPK2 influence inflammatory disease. As NF-?B regulated genes, NOD2 and RIPK2 expression and activity is heightened during inflammation, and hyperactivation of WT NOD2 and WT RIPK2 can drive the pathophysiology of diseases as diverse as multiple sclerosis, rheumatoid arthritis, asthma and inflammatory bowel disease. This therefore highlights the unique balance that must be maintained by both NOD2 and RIPK2 to maintain physiologic inflammation while avoiding pathologic inflammation. Our work under this grant has been directed at understanding the molecular basis for NOD2:RIPK2 signal transduction and to translate that work to clinical medicine. In the current grant application, we aim to study the interaction of the inflammasome?s interaction with the NOD2:RIPK2 signaling pathway, the ubiquitin dynamics regulating this pathway and a novel mechanism of downregulation of this pathway.

Public Health Relevance

Lay Summary As humans, we are constantly exposed to pathogens. Whether it?s from shaking a neighbor?s hand or being coughed on in an airplane, our bodies must recognize and react to everyday exposures to viruses, bacteria and fungi. Given this, it is important to respond in a manner appropriate to the stimulus. Too much of an inflammatory response can cause autoinflammatory diseases like Crohn?s disease, multiple sclerosis and psoriasis while too little of an inflammatory response can cause immunodeficiency. This grant application aims to better understand this balance through the study of the NOD2:RIPK2:XIAP pathway. The last decade of this granting period have helped us better understand how this pathway works to both prevent and predispose to disease, and in fact, pharmacologic agents are now under development based on this work. In the next granting period, we hope to better settle key controversies in the field such that we can better predict potential drug associated toxicities as we move our inhibitors forward clinically.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Zhao, Xiaoli
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Schools of Medicine
United States
Zip Code
Rathkey, Joseph K; Zhao, Junjie; Liu, Zhonghua et al. (2018) Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Sci Immunol 3:
Yang, Jie; Liu, Zhonghua; Wang, Chuanping et al. (2018) Mechanism of gasdermin D recognition by inflammatory caspases and their inhibition by a gasdermin D-derived peptide inhibitor. Proc Natl Acad Sci U S A 115:6792-6797
Liu, Zhonghua; Wang, Chuanping; Rathkey, Joseph K et al. (2018) Structures of the Gasdermin D C-Terminal Domains Reveal Mechanisms of Autoinhibition. Structure 26:778-784.e3
Perez, Jessica M; Chen, Yinghua; Xiao, Tsan S et al. (2018) Phosphorylation of the E3 ubiquitin protein ligase ITCH diminishes binding to its cognate E2 ubiquitin ligase. J Biol Chem 293:1100-1105
Liu, Xia; Taftaf, Rokana; Kawaguchi, Madoka et al. (2018) Homophilic CD44 Interactions Mediate Tumor Cell Aggregation and Polyclonal Metastasis in Patient-Derived Breast Cancer Models. Cancer Discov :
Chirieleison, Steven M; Rathkey, Joseph K; Abbott, Derek W (2018) Unique BIR domain sets determine inhibitor of apoptosis protein-driven cell death and NOD2 complex signal specificity. Sci Signal 11:
Zhang, Cun-Jin; Jiang, Meiling; Zhou, Hao et al. (2018) TLR-stimulated IRAKM activates caspase-8 inflammasome in microglia and promotes neuroinflammation. J Clin Invest 128:5399-5412
Dziedzic, Slawomir A; Su, Zhenyi; Jean Barrett, Vica et al. (2018) ABIN-1 regulates RIPK1 activation by linking Met1 ubiquitylation with Lys63 deubiquitylation in TNF-RSC. Nat Cell Biol 20:58-68
Chirieleison, Steven M; Marsh, Rebecca A; Kumar, Prathna et al. (2017) Nucleotide-binding oligomerization domain (NOD) signaling defects and cell death susceptibility cannot be uncoupled in X-linked inhibitor of apoptosis (XIAP)-driven inflammatory disease. J Biol Chem 292:9666-9679
Rathkey, Joseph K; Benson, Bryan L; Chirieleison, Steven M et al. (2017) Live-cell visualization of gasdermin D-driven pyroptotic cell death. J Biol Chem 292:14649-14658

Showing the most recent 10 out of 33 publications