Mechanistic elucidation of inflammasome biology
EMSL Project ID
51001
Abstract
Innate immunity comprises ancient and evolutionarily conserved biological pathways that are imperative for the recognition of pathogens and endogenous damage. One such major signaling pathway utilizes the ATPase domain-containing proteins known as NLRs, which are large multidomain proteins (> 100 kDa) usually composed of a nucleotide-binding domain (NBD), a leucine-rich repeat (LRR) domain, and either a pyrin domain (PYD) or a caspase recruitment domain (CARD) for interaction with adaptor proteins and/or caspase-1 to form inflammasomes to result in caspase-1 activation. Caspase-1 activation leads to cytokine maturation by cleaving pro-IL-1 and pro-IL-18, and pyroptotic cell death by cleaving gasdermin D (GSDMD) to protect the host. However, aberrant inflammasome signaling is associated with numerous human diseases, both rare genetic autoinflammatory diseases and common diseases such as cardiovascular disease, gout, Alzheimer’s disease and inflammatory bowel disease. Thus, elucidating the molecular mechanisms governing inflammasome biology will help the development of new therapeutics.My lab has been focusing on the structural biology of inflammasomes, having solved the first activated NLR inflammasome (NLRC4) structure (Cell 2015), the first NLRP3 structure (Nature 2019), the first PYD and CARD filament structures in inflammasomes (Cell 2014, NSMB 2016, PNAS 2019), and the first GSDM pore structure (Nature 2018). In this application, we propose new directions on the structural biology of inflammasomes. Completion of these projects will have a high impact in both basic science and in improving human health.
Project Details
Start Date
2019-08-01
End Date
2021-03-17
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Hollingsworth L.R., H. Sharif, A.R. Griswold, P. Fontana, J. Mintseris, K.A. Dagbay, and J.A. Paulo, et al. 2020. "DPP9 Directly Sequesters the NLRP1 C-terminus to Repress Inflammasome Activation." bioRxiv preprint.n Mintseris, Kevin B. Dagbay, Joao A. Paulo, Steven P. Gygi, Daniel A. Bachovchin?, Hao Wu?
L. Robert Hollingsworth, Liron David, Yang Li, Andrew R. Griswold, Humayun Sharif, Pietro Fontana, Tian-Min Fu, Jianbin Ruan, Daniel A. Bachovchin, Hao Wu (2020) Preprint on bioRxiv.