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Licensed Unlicensed Requires Authentication Published by De Gruyter August 21, 2013

Granule proteases of hematopoietic cells, a family of versatile inflammatory mediators – an update on their cleavage specificity, in vivo substrates, and evolution

  • Lars Hellman

    Lars Hellman studied molecular biology at Uppsala University and received a PhD in Microbiology in 1985. After 2 years of post doc at MIT and Brandeis University in the US, he started an independent research group at Uppsala University in 1988. He was appointed a full professor of Molecular and Comparative Immunology at Uppsala University in 2000. His group studies molecular aspects of atopic allergies, with focus on IgE-structure and evolution, granule associated serine proteases of mast cells and other hematopoietic cells, and in developing therapeutic vaccines for the treatment of allergy.

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    and Michael Thorpe

    Michael Thorpe received his bachelor’s degree in biology from Lancaster University (UK), in 2005. After finishing his master’s degree in infection biology and immunology from Uppsala University (Sweden) in 2009, he carried on as a PhD student in Lars Hellman’s lab. He is currently in his final year of research and focuses on aspects related to hematopoietic serine proteases.

From the journal Biological Chemistry

Abstract

Cells from several of the hematopoietic cell lineages including mast cells, basophils, neutrophils, cytotoxic T cells, and natural killer (NK) cells store proteases at very high levels within their cytoplasmic granules. In mast cells, these proteases can account for up to 35% of the total cellular protein, and the absolute majority of these belong to the chymotrypsin-related serine protease family. A number of very diverse functions have been identified for these proteases, including apoptosis induction, blood pressure regulation, inactivation of insect and snake toxins, intestinal parasite expulsion, killing of bacteria and fungi, induction, mobilization, or degradation of cytokines, and the degradation of connective tissue components. A very broad spectrum of primary cleavage specificities has also been observed, including chymase, tryptase, asp-ase, elastase, and met-ase specificities, which highlights the large flexibility in the active site of these proteases. Mast cells primarily express chymases and tryptases with chymotryptic or tryptic primary cleavage specificities, respectively. Neutrophils have several enzymes with chymase, elastase, and tryptase specificities. T cells and NK cells express between 5 and 14 different granzymes, depending on the species, and these enzymes have tryptase, asp-ase, chymase, and met-ase specificities. This review focuses on the appearance of these proteases during vertebrate evolution, their primary and extended cleavage specificities, and their potential in vivo substrates. The in vivo substrates and functions are a particular challenging issue because several of these enzymes have a relatively broad specificity and may therefore cleave a wide range of different substrates.


Corresponding author: Lars Hellman, Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, Box 596, S-751 24 Uppsala, Sweden, e-mail:

About the authors

Lars Hellman

Lars Hellman studied molecular biology at Uppsala University and received a PhD in Microbiology in 1985. After 2 years of post doc at MIT and Brandeis University in the US, he started an independent research group at Uppsala University in 1988. He was appointed a full professor of Molecular and Comparative Immunology at Uppsala University in 2000. His group studies molecular aspects of atopic allergies, with focus on IgE-structure and evolution, granule associated serine proteases of mast cells and other hematopoietic cells, and in developing therapeutic vaccines for the treatment of allergy.

Michael Thorpe

Michael Thorpe received his bachelor’s degree in biology from Lancaster University (UK), in 2005. After finishing his master’s degree in infection biology and immunology from Uppsala University (Sweden) in 2009, he carried on as a PhD student in Lars Hellman’s lab. He is currently in his final year of research and focuses on aspects related to hematopoietic serine proteases.

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Received: 2013-6-23
Accepted: 2013-8-18
Published Online: 2013-08-21
Published in Print: 2014-01-01

©2014 by Walter de Gruyter Berlin Boston

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