Department of Medicine, Division of Infectious Diseases
M.D., Internal Medicine & Infectious Diseases
- Molecular mechanisms of activation of NLR family signaling proteins
- Mechanisms of NLRP3-inflammasome mediated programmed necrotic cell death (pyronecrosis) and caspase-1 activation
- Role of NLRP3-inflammasome signaling in infectious disease pathogenesis
The ability to recognize pathogens and initiate inflammatory and immunologic processes to control their spread relies on innate immune system signaling. One of the most recently identified pathogen-sensing signaling pathways involves the activation of the inflammasome, a macromolecular complex responsible for proteolytic processing of several immature cytokines (IL-1b and IL-18 in particular). The protein NLRP3 acts as a central scaffold during in the assembly of the inflammasome in response to numerous inflammatory stimuli known to induce IL-1b secretion.
We have shown that NLRP3 is an ATP binding protein and that nucleotide binding activity is critical to the ability of NLRP3 initiate inflammasome assembly. Mutations in the nucleotide-binding domain of NLRP3 can cause inherited periodic fever syndromes. We are engaged in determining how nucleotide binding by NLRP3 is regulated and how this regulation controls signaling through this protein in response to infectious agents and mutations that induce pathologic inflammation.
In addition to cytokine processing, signaling through NLRP3 activates a novel necrotic cell death program, called pyronecrosis. Cell death programs are critical signaling pathways in multicellular organisms and represent mechanisms by which individual cells are sacrificed for the good of an organism. We hypothesize that pyronecrosis plays a physiologic role in the signaling by the NLRP3-inflammasome. We are seeking to determine the mechanisms by which the NLRP3-inflammasome executes this novel program of cell death.
We have also recently discovered that virulence factors from some pathogens (including S. aureus and N. gonorrhoeae) activate the NLRP3 inflammasome. We are now trying to determine the role of NLRP3 signaling in the pathogenesis of infectious processes caused pathogens expressing these factors.
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Duncan, J. A., Bergstralh, D. T., Wang, Y., Willingham, S. B., Ye, Z., Zimmermann, A., and Ting, J. P., (2007), Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling, Proc. Natl. Acad. Sci. USA 104, 8041-8046.
Willingham, S. B., Bergstralh, D. T., O’Connor, W., Taxman, D. J., Morrison, A. C., Duncan, J. A., Mohanish, D., Hoffman, H., and Ting, J. P., (2007), Microbial pathogen-induced necrotic-like cell death mediated by CIAS1/cryopyin and ASC, Cell Host and Microbe. 2, 147-159.
Moore, C. B., Bergstralh, D. T., Duncan, J. A., Lei, Y., Morrison, T.E., Accavitti-Loper M. A., Madden, V. J., Sun, L., Lich, J. D., Heise, M. T., Chen, Z., Ting, J. P., (2008), NLRX1 is a regulator of mitochondrial antiviral immunity, Nature 451, 573-577.
Duncan, J. A., Gao, X., Huang, M., O’connor, B.P., Thomas, C. E., Willingham, S. B., Bergstralh, D. T., Jarvis, G. A., Sparling, P. F., and Ting, J. P., (2009), Neisseria gonorrhoeae activates the proteinase Cathepsin B to mediate the signaling activities of the NLRP3 and ASC - containing inflammasome, J. Immunology 182 (10), 6460-6469
Craven, R. R., Gao, X., Allen, I. C., Gris, D., Wardenburg, J. B., McElvania-TeKippe, E., Ting, J. P., and Duncan, J. A. (2009) Staphylococcus aureus α-Hemolysin Activates the NLRP3-Inflammasome in Human and Mouse Monocytic Cells. PLoS ONE 4(10): e7446.