Cysteine Proteases in Apoptosis

Summary

Principal Investigator: EMAD ALNEMRI
Affiliation: Thomas Jefferson University
Country: USA
Abstract: DESCRIPTION (provided by applicant): Caspase-1 is a member of a family of aspartate-specific cysteine proteases, known as the caspase family, involved in apoptosis and inflammation. Recent studies revealed that caspase-1 is activated within large protein complexes or assemblies called the inflammasomes. The inflammasomes are composed of several adaptor proteins that interact with caspase-1 and induce its oligomerization and activation. Preliminary evidence from the applicant's lab suggest that pyrin, a protein mutated in the auto- inflammatory disease Familial Mediterranean fever (FMF), plays a major role in inflammation by assembling an inflammasome complex with the adaptor protein ASC, and procaspase-1 leading to ASC oligomerization, caspase-1 activation and IL-1[unreadable] processing. Pyrin also appears to play an important role in apoptosis as macrophages from pyrin-truncation mice exhibit a defect in apoptosis compared to macrophages from wildtype mice in response to IL-4 and LPS stimulation. Evidence suggests that the inflammatory and perhaps the apoptotic activities of pyrin are regulated by two cytoskeleton associated proteins known as PSTPIP1 and PSTPIP2. Missense mutations in these proteins are associated with two further auto-inflammatory diseases, known as pyogenic arthritis, pyoderma gangrenosum, acne syndrome (PAPA) and chronic multifocal osteomyelitis (cmo) syndrome, respectively. In this competing continuation application three specific aims are proposed to study the physiological role of pyrin in apoptosis and inflammation and the role of the cytoskeleton in these two pyrin pathways. In the first specific aim, the role of pyrin in caspase-1 activation will be investigated through detailed biochemical and biological studies in cell-based and cell-free reconstitution systems and human and mouse macrophage cell lines. In the second specific aim, experiments are proposed to characterize the interaction of PSTPIP1 and PSTPIP2 with pyrin and determine their ability to regulate caspase-1 activation in human and mouse cells. In the third specific aim, biological, biochemical and genetic approaches will be used to elucidate the mechanism by which pyrin regulates apoptosis. Understanding the interplay of the pyrin-mediated inflammatory and apoptotic responses and the mechanism of activation of caspase-1 by pyrin is likely to contribute important insights into the role of pyrin in innate immunity and apoptosis, with obvious potential clinical applications. Public Health Relevance Statement: Mutations in the genes encoding pyrin and the pyrin-associated protein PSTPIP1 are associated with severe autoinflammatory diseases in humans. This research will investigate the physiological function of pyrin to elucidate its role in normal cellular function and how disease-associated mutations alter its function. The results of this research will help in the design and discovery of effective therapeutics to treat autoinflammatory diseases.
Funding Period: ----------------1996 - ---------------2013-
more information: NIH RePORT

Top Publications

  1. pmc The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity
    Sangjun Park
    Department of Microbiology, Brain Korea 21 Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 120 752, Korea
    J Immunol 191:4358-66. 2013
  2. pmc Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome
    Teresa Fernandes-Alnemri
    Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
    J Immunol 191:3995-9. 2013
  3. pmc Ribotoxic stress through p38 mitogen-activated protein kinase activates in vitro the human pyrin inflammasome
    Je Wook Yu
    Department of Biochemistry and Molecular Biology and the Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
    J Biol Chem 288:11378-83. 2013
  4. pmc Restoration of ASC expression sensitizes colorectal cancer cells to genotoxic stress-induced caspase-independent cell death
    Sujeong Hong
    Department of Microbiology, Yonsei University College of Medicine, Seoul, Republic of Korea
    Cancer Lett 331:183-91. 2013
  5. pmc Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation
    Christine Juliana
    Department of Biochemistry and Molecular Biology and the Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
    J Biol Chem 287:36617-22. 2012
  6. pmc Critical roles of ASC inflammasomes in caspase-1 activation and host innate resistance to Streptococcus pneumoniae infection
    Rendong Fang
    Department of Microbiology, Kyoto University Graduate School of Medicine, Kyoto 606 8501, Japan
    J Immunol 187:4890-9. 2011
  7. pmc Cutting edge: mutation of Francisella tularensis mviN leads to increased macrophage absent in melanoma 2 inflammasome activation and a loss of virulence
    Tyler K Ulland
    Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA
    J Immunol 185:2670-4. 2010
  8. pmc Involvement of the AIM2, NLRC4, and NLRP3 inflammasomes in caspase-1 activation by Listeria monocytogenes
    Jianghong Wu
    Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
    J Clin Immunol 30:693-702. 2010
  9. pmc Sensing cytoplasmic danger signals by the inflammasome
    Emad S Alnemri
    Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
    J Clin Immunol 30:512-9. 2010
  10. pmc The AIM2 inflammasome is critical for innate immunity to Francisella tularensis
    Teresa Fernandes-Alnemri
    Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
    Nat Immunol 11:385-93. 2010

Scientific Experts

  • Emad S Alnemri
  • Teresa Fernandes-Alnemri
  • Je Wook Yu
  • Christine Juliana
  • Jianghong Wu
  • Pinaki Datta
  • Inhwa Hwang
  • Sangjun Park
  • Sujeong Hong
  • Seokwon Kang
  • Andrew Farias
  • Katherine A Fitzgerald
  • Rendong Fang
  • Tyler K Ulland
  • Isabelle Jeru
  • Leobaldo Solorzano
  • Eicke Latz
  • Franz G Bauernfeind
  • Won Keun Lee
  • Yun Sun Lee
  • You Sun Kim
  • Junji Sagara
  • Connor Anderson
  • Fengsong Qin
  • Yanting Xu
  • Masao Mitsuyama
  • Eduardo Hernandez-Cuellar
  • Kohsuke Tsuchiya
  • Yanna Shen
  • Ikuo Kawamura
  • Takeshi Yamamoto
  • Huixin Qu
  • Shunsuke Sakai
  • Sita R Dewamitta
  • Hideki Hara
  • RuiLi Yang
  • Serge Amselem
  • Philippe Duquesnoy
  • Charles P Scott
  • Andrew A Quong
  • Margaret McCormick
  • Margaret R Ketterer
  • Sylvain Normand
  • Blake W Buchan
  • William M Nauseef
  • Sandrine Marlin
  • Carlisle P Landel
  • Teresa Fernandes Alnemri
  • Michael A Apicella
  • Véronique Hentgen
  • David K Meyerholz
  • Bradley D Jones
  • Erin McDermott
  • Robin Dhote
  • Laurence Eisenlohr
  • Laurence Cuisset
  • Florence Dastot-Le Moal
  • Fayyaz S Sutterwala
  • Jean Claude Lecron
  • Gaëlle Le Borgne
  • Rong Meng
  • Gilles Grateau
  • Emmanuelle Cochet
  • Lan Huang
  • David Speert
  • Andrea Stutz
  • Kelly MacDonald
  • Gabor Horvath
  • Brian G Monks
  • Veit Hornung

Detail Information

Publications14

  1. pmc The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity
    Sangjun Park
    Department of Microbiology, Brain Korea 21 Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 120 752, Korea
    J Immunol 191:4358-66. 2013
    ..Taken together, our results suggest that MAVS facilitates the recruitment of NLRP3 to the mitochondria and may enhance its oligomerization and activation by bringing it in close proximity to mitochondrial reactive oxygen species. ..
  2. pmc Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome
    Teresa Fernandes-Alnemri
    Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
    J Immunol 191:3995-9. 2013
    ..These findings define the pathways that lead to rapid NLRP3 activation and identify IRAK1 as a critical mediator of a transcription-independent,inflammasome-dependent early warning response to pathogenic infection. ..
  3. pmc Ribotoxic stress through p38 mitogen-activated protein kinase activates in vitro the human pyrin inflammasome
    Je Wook Yu
    Department of Biochemistry and Molecular Biology and the Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
    J Biol Chem 288:11378-83. 2013
    ..Together, our results indicate that ribotoxic stress activates the human pyrin inflammasome through a mechanism that requires p38 MAPK signaling and microtubule stability...
  4. pmc Restoration of ASC expression sensitizes colorectal cancer cells to genotoxic stress-induced caspase-independent cell death
    Sujeong Hong
    Department of Microbiology, Yonsei University College of Medicine, Seoul, Republic of Korea
    Cancer Lett 331:183-91. 2013
    ..Thus, our data suggest that ASC expression in cancer cells is an important factor in determining their susceptibility to chemotherapy...
  5. pmc Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation
    Christine Juliana
    Department of Biochemistry and Molecular Biology and the Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
    J Biol Chem 287:36617-22. 2012
    ....
  6. pmc Critical roles of ASC inflammasomes in caspase-1 activation and host innate resistance to Streptococcus pneumoniae infection
    Rendong Fang
    Department of Microbiology, Kyoto University Graduate School of Medicine, Kyoto 606 8501, Japan
    J Immunol 187:4890-9. 2011
    ..pneumoniae, with impaired secretion of IL-1β and IL-18 into the bronchoalveolar lavage after intranasal infection, suggesting that ASC inflammasomes contribute to the protection of host from infection with PLY-producing S. pneumoniae...
  7. pmc Cutting edge: mutation of Francisella tularensis mviN leads to increased macrophage absent in melanoma 2 inflammasome activation and a loss of virulence
    Tyler K Ulland
    Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA
    J Immunol 185:2670-4. 2010
    ..This study demonstrates that mviN limits F. tularensis-induced absent in melanoma 2 inflammasome activation, which is critical for its virulence in vivo...
  8. pmc Involvement of the AIM2, NLRC4, and NLRP3 inflammasomes in caspase-1 activation by Listeria monocytogenes
    Jianghong Wu
    Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
    J Clin Immunol 30:693-702. 2010
    ..Taken together, our results indicate that Listeria infection is sensed by multiple inflammasomes that collectively orchestrate a robust caspase-1 activation and proinflammatory response...
  9. pmc Sensing cytoplasmic danger signals by the inflammasome
    Emad S Alnemri
    Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
    J Clin Immunol 30:512-9. 2010
    ..Absent in melanoma 2 (AIM2) is a newly discovered PRR involved in the sensing of dangerous cytosolic DNA produced by infection with DNA viruses...
  10. pmc The AIM2 inflammasome is critical for innate immunity to Francisella tularensis
    Teresa Fernandes-Alnemri
    Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
    Nat Immunol 11:385-93. 2010
    ..tularensis infection or the presence of cytoplasmic DNA. Our study identifies AIM2 as a crucial sensor of F. tularensis infection and provides genetic proof of its critical role in host innate immunity to intracellular pathogens...
  11. doi Functional consequences of a germline mutation in the leucine-rich repeat domain of NLRP3 identified in an atypical autoinflammatory disorder
    Isabelle Jeru
    INSERM, U933, Universite Pierre et Marie Curie Paris 6, UMR S933, and Assistance Publique Hopitaux de Paris, Hopital Armand Trousseau, 75571 Paris, France
    Arthritis Rheum 62:1176-85. 2010
    ....
  12. pmc Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome
    Christine Juliana
    Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
    J Biol Chem 285:9792-802. 2010
    ..Our results thus elucidate the molecular mechanism for the therapeutic anti-inflammatory activity of parthenolide and identify vinyl sulfones as a new class of potential therapeutics that target the NLRP3 inflammasome...
  13. pmc Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression
    Franz G Bauernfeind
    Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA
    J Immunol 183:787-91. 2009
    ..Signals provided by NF-kappaB activators are necessary but not sufficient for NLRP3 activation, and a second stimulus such as ATP or crystal-induced damage is required for NLRP3 activation...
  14. pmc AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA
    Teresa Fernandes-Alnemri
    Department of Biochemistry and Molecular Biology, Center for Apoptosis Research, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
    Nature 458:509-13. 2009
    ..This study identifies AIM2 as an important inflammasome component that senses potentially dangerous cytoplasmic DNA, leading to activation of the ASC pyroptosome and caspase-1...