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Structural and mechanistic studies of the CARD8 inflammasome


EMSL Project ID
50911

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 axis termed the inflammasome pathway recognizes these forms of innate danger and forms large supramolecular signaling complexes (inflammasomes) that potentiate the inflammatory response. Proteins comprising inflammasomes often contain either a pyrin domain (PYD) or a caspase recruitment domain (CARD) for interaction with adaptor proteins and/or caspase-1, resulting 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. Herein, we propose to solve cryo-EM structures of signaling components in the inflammasome pathway to better understand the regulation governing this critical host defense mechanism, and to enable rational therapeutic design against inflammatory targets. We are requesting several days of Talos Arctica time for cryo-EM screening, in addition to data collection on a Titan Krios. Structures will inform new biological hypotheses and will drive the design of cellular and biophysical experiments that elucidate mechanism in the inflammasome pathway.

Project Details

Start Date
2019-08-01
End Date
2020-01-31
Status
Closed

Team

Principal Investigator

Hao Wu
Institution
Boston Children's Hospital

Team Members

Theo Humphreys
Institution
Oregon Health & Science University

Humayun Sharif
Institution
Boston Children's Hospital

Louis Hollingsworth
Institution
Boston Children's Hospital

Related Publications

Hollingsworth L.R., L. David, Y. Li, A.R. Griswold, H. Sharif, P. Fontana, and T. Fu, et al. 2020. "Novel Mode of Filament Formation in UPA-promoted CARD8 and NLRP1 Inflammasomes." bioRxiv preprint.
H. Sharif-, L.R. Hollingsworth-, A.R. Griswold-, J. C. Hsiao, Q. Wang, D. A. Bachovchin, and H. Wu. 2021. "Structural mechanism of CARD8 regulation by DPP9." bioRxiv preprint.
L.R. Hollingsworth, L. David, Y. Li, A.R. Griswold, J. Ruan, H. Sharif, P. Fontana, E. Orth-He, T. M. Fu, D. A. Bachovchin, and H. Wu, 2021. "Mechanism of filament formation in UPA-promoted CARD8 and NLRP1 inflammasomes". Nature Communications. 12 (189)