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Rui Yang Master of Biology thesis.pdf (3.79 MB)

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Interaction between caspases and their substrates in the inflammasome signaling pathway

Yang, Rui
http://rave.ohiolink.edu/etdc/view?acc_num=case1559917811566556

Abstract Details

2019, Master of Sciences, Case Western Reserve University, Biology.
Caspases are a family of cysteine proteases that play an important role in anti-microbial immune responses and inflammatory disorders. They can be divided into several subfamilies, one of which is the inflammatory caspases, including caspases-1, -4, -5 and -11. Inflammatory caspases are activated by the inflammasome signaling pathways. Active caspase-1 is able to convert pro interleukin-1 beta (pro-IL-1 beta to its mature form, which facilitates its secretion. Recent studies identified the gasdermin D (GSDMD) protein as a substrate of caspases-1, -4, -5 and -11 and a mediator of pyroptotic cell death. Both pro-IL 1 beta and GSDMD are substrates of caspases downstream of the inflammasome signaling pathway. In this study, I investigated the molecular mechanisms of the interaction between caspases and these two substrates. Caspase inhibitors are useful tools for studying both apoptosis and pyroptosis. Based on our understanding of the mechanisms for caspase gasdermin D recognition, we designed an inhibitor Ac-FLTD-CMK, which is specific for the inflammatory caspases. The inhibitor consists of an FLTD peptide from the GSDMD cleavage site, which is recognizable by inflammatory caspases. The C-terminus of the peptide is modified by a chloromethylketone (CMK) moiety to react with the active site cysteine residue from caspases. Our in vitro caspase inhibition data demonstrates that the Ac-FLTD-CMK inhibitor is of high potency against caspases-1, -4, -5 and -11, but did not inhibit the apoptotic caspase-3. Ac-FLTD-CMK inhibits pyroptosis in both the NLRP3 and non-canonical inflammasome pathways. Crystal structures of caspase-1 and Ac-FLTD-CMK complex revealed the molecular mechanisms of how the inhibitor binds and inhibits inflammatory caspases. Our study sheds light on the mechanisms of GSDMD recognition by caspases and provides a novel tool for investigating inflammasomes and pyroptosis.
Sarah Bagby (Committee Chair)
Tsan Xiao (Committee Member)
Emmitt Jolly (Committee Member)
Christopher Cullis (Advisor)
81 p.
Biology

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Citations

  • Yang, R. (2019). Interaction between caspases and their substrates in the inflammasome signaling pathway [Master's thesis, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1559917811566556

    APA Style (7th edition)

  • Yang, Rui. Interaction between caspases and their substrates in the inflammasome signaling pathway. 2019. Case Western Reserve University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1559917811566556.

    MLA Style (8th edition)

  • Yang, Rui. "Interaction between caspases and their substrates in the inflammasome signaling pathway." Master's thesis, Case Western Reserve University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1559917811566556

    Chicago Manual of Style (17th edition)

case1559917811566556
148
© 2019, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.