Caspase-1 is an important component of the innate immune response against pathogenic infection and cellular stresses. Activation of caspase-1 can lead to processing of the inactive pro-IL-12 and pro-IL-18 to produce the active cytokines IL-12 and IL-18, respectively, which are potent mediators of inflammation that stimulate fever, recruitment and activation of immune cells, production of secondary cytokines and cellular proliferation. Caspase-1 activation can also lead to an inflammatory form of cell death called pyroptosis. The applicant's laboratory demonstrated recently that this form of cell death is mediated by the caspase-1 adaptor protein ASC, which assembles a supramolecular structure termed the pyroptosome that activates caspase-1 during pyroptosis in response to diverse pro-inflammatory and stress signals. They have also elucidated the role of pyrin, a protein mutated in familial Mediterranean fever, in caspase-1 activation and inflammation in the human auto-inflammatory PAPA syndrome, and demonstrated that pyrin is a homotrimeric cytosolic receptor for the cytoskeleton- organizing protein PSTPIP1. Ligation by PSTPIP1 activates pyrin by unmasking of its PYD domain, which then interacts with ASC and facilitates ASC oligomerization into the active pyroptosome. In this application specific aims are proposed to extend these ongoing studies to further investigate the regulation and molecular determinants of the interaction between PSTPIP1 and pyrin. In particular, the aims will focus on characterizing the exact role of the protein-tyrosine phosphatase PTP-PEST and tyrosine kinase c-Abl, both of which have been shown to interact with PSTPIP1, in the pyrin-mediated caspase-1 activation pathway. It is also proposed to characterize novel upstream activators of the ASC pyroptosome and further investigate the role TLR2, TLR4, cryopyrin and caspase-1-mediated proteolysis in macrophage pyroptosis. Finally, studies are proposed to investigate the potential use of the in vitro ASC pyroptosome assembly as a high throughput screen to identify small molecule therapeutics to inhibit and treat inflammation.

Public Health Relevance

Inflammation is a key process in the innate immune response to infections and cellular stress. This research focuses on understanding the role of key cellular proteins in the complex molecular and cellular inflammatory mechanisms. The results of this research will help in the design and discovery of effective therapeutics to treat inflammation associated with aging, auto-inflammatory disease and chronic inflammatory diseases.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Finkelstein, David B
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Thomas Jefferson University
Schools of Medicine
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Fernandes-Alnemri, Teresa; Kang, Seokwon; Anderson, Connor et al. (2013) Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome. J Immunol 191:3995-9
Park, Sangjun; Juliana, Christine; Hong, Sujeong et al. (2013) The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity. J Immunol 191:4358-66
Kang, S; Louboutin, J-P; Datta, P et al. (2013) Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging. Cell Death Differ 20:259-69
Yu, Je-Wook; Farias, Andrew; Hwang, Inhwa et al. (2013) Ribotoxic stress through p38 mitogen-activated protein kinase activates in vitro the human pyrin inflammasome. J Biol Chem 288:11378-83
Hong, Sujeong; Hwang, Inhwa; Lee, Yun-Sun et al. (2013) Restoration of ASC expression sensitizes colorectal cancer cells to genotoxic stress-induced caspase-independent cell death. Cancer Lett 331:183-91
Hashimoto, Yoshifumi; Hosoda, Nao; Datta, Pinaki et al. (2012) Translation termination factor eRF3 is targeted for caspase-mediated proteolytic cleavage and degradation during DNA damage-induced apoptosis. Apoptosis 17:1287-99
Juliana, Christine; Fernandes-Alnemri, Teresa; Kang, Seokwon et al. (2012) Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem 287:36617-22
Fang, Rendong; Tsuchiya, Kohsuke; Kawamura, Ikuo et al. (2011) Critical roles of ASC inflammasomes in caspase-1 activation and host innate resistance to Streptococcus pneumoniae infection. J Immunol 187:4890-9
Wu, Jianghong; Fernandes-Alnemri, Teresa; Alnemri, Emad S (2010) Involvement of the AIM2, NLRC4, and NLRP3 inflammasomes in caspase-1 activation by Listeria monocytogenes. J Clin Immunol 30:693-702
Juliana, Christine; Fernandes-Alnemri, Teresa; Wu, Jianghong et al. (2010) Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome. J Biol Chem 285:9792-802

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