The biology of cytotoxic cell granule exocytosis pathway: granzymes have evolved to induce cell death and inflammation |
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| Institution: | 1. Dpto. Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Spain;2. Fundación Aragón I+D/Gobierno de Aragón, Zaragoza, Spain;3. Metschnikoff laboratory, Max-Planck Institute for Immunobiology, Freiburg, Germany;4. Institute of Molecular Medicine and Cell Research, Center for Biochemistry and Molecular Research, Freiburg, Germany;5. Institut für Immunologie, Universitätsklinikum Heidelberg, Heidelberg, Germany;6. Viral Immunology, Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Canberra, Australia;7. Department of Medicine, NorthShore University HealthSystem Research Institute, Evanston, IL, USA;1. Division of Critical Care Medicine, Department of Pediatrics, School of Medicine, Washington University, St Louis, MO;2. Department of Biochemistry and Molecular Biophysics, School of Medicine, Washington University, St Louis, MO;3. Division of Hematology and Oncology, Department of Pediatrics, School of Medicine, Washington University, St Louis, MO;4. Division of Genetics and Genomic Medicine, Department of Pediatrics, School of Medicine, Washington University, St Louis, MO;5. Department of Chemistry, College of Arts and Sciences, Washington University, St Louis, MO;1. Institut Curie, Centre de Recherche, 26 rue d’Ulm, Paris F-75248, France;2. INSERM U932, Paris F-75248, France;3. Paris Sciences et Lettres (PSL*), Paris F-75005, France;1. Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, United States;2. Department of Pathology, University of Virginia, Charlottesville, VA, United States;3. Department of Biochemistry, Molecular Biology, and Genetics, University of Virginia, Charlottesville, VA, United States;4. Department of Surgery, University of Virginia, Charlottesville, VA, United States;5. Department of Medicine, Division of Cardiovascular Medicine, University of Virginia, Charlottesville, VA, United States;6. Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United States;7. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, United States;3. From the Department of Molecular and Experimental Medicine and;5. Light Microscopy Core Facility, The Scripps Research Institute, La Jolla, California 92037 and;4. Cancer Center Microscopy Shared Resource, University of California San Diego, La Jolla, California 92093;1. International Collaboration on Repair Discoveries (ICORD) Centre, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada;2. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada;3. British Columbia Professional Firefighters’ Burn and Wound Healing Group, Vancouver, British Columbia, Canada;4. Division of Respirology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada;5. Division of Dermatology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada |
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| Abstract: | The granule exocytosis pathway of cytotoxic lymphocytes (Tc and NK cells) is critical for control of tumor development and viral infections. Granule-associated perforin and granzymes are key components in Tc cell-mediated function(s). On the basis of studies that showed granzymes A, B, C, K and M, to induce apoptosis in vitro, all granzymes were thought to also induce cell death in vivo. This review summarizes our present understanding of the biological processes elicited by purified granzyme A and granzyme as well as the processes induced by the more physiologically relevant cytotoxic cells secreting these proteases. The combined evidence supports the concept that the granule secretion pathway is not mono-specific but rather poly-functional including induction of pro-inflammatory cytokines, besides their widely appreciated apoptotic properties. |
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