J Tschopp

University of Lausanne

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Michael D. Pierschbacher

American Life Science Pharmaceuticals (United States)

Lars E. French

Ludwig-Maximilians-Universität München

Curt Mazur

Ionis Pharmaceuticals (United States)

Dieter E. Jenne

Max Planck Institute of Neurobiology

Olivier Krähenbühl

University of Lausanne

Manuel C. Peitsch

Philip Morris International (Switzerland)

Randy Schekman

Howard Hughes Medical Institute

W. S. Craig

Oklahoma State University Center for Health Sciences

H. Isliker

Aristotle University of Thessaloniki

Gönül Veliçelebi

CalciMedica (United States)

Cooperative Institutions

University of Lausanne

Inserm

Salk Institute for Biological Studies

University of Geneva

Howard Hughes Medical Institute

National Institutes of Health

Centre National de la Recherche Scientifique

University Hospital of Geneva

University of Michigan–Ann Arbor

University of California, San Diego

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Identification and sequencing of cDNA clones encoding the granule-associated serine proteases granzymes D, E, and F of cytolytic T lymphocytes.

Proceedings of the National Academy of Sciences (1988)

Dieter E. Jenne C Rey Jacques‐Antoine Haefliger Bin Qiao Peter Groscurth

Cytoplasmic granules of cytolytic T lymphocytes contain at least six related serine esterases (granzymes) that are released together with perforin, a pore-forming protein related to complement component C9, during target-cell lysis. Polyclonal antibodies were used to isolate a large number of cDNA clones from an expression library derived from cytolytic-T-cell mRNA. Three distinct full-length cDNA clones coding for granzymes D, E, and F were identified by restriction site mapping and nucleotide sequencing. The three deduced amino acid sequences are highly similar to one another (between 72% and 90% amino acid identities) and to the sequences of granzymes B and C, cathepsin G, and rat mast-cell proteases I and II (between 43% and 57% amino acid identities). Cysteine residues capable of forming intramolecular disulfide bonds are conserved, as are the catalytic-site residues characteristic of serine proteases. Comparison of the cDNA-derived protein sequences with the amino termini of the isolated granzymes provides evidence that they are stored in a fully processed, activated form after removal of the signal peptide and two additional residues (propeptide) at the amino terminus. Immunoelectron microscopic studies demonstrated that granzymes D, E, and F are present in the same morphologically distinct cytoplasmic granules in which perforin has been found previously.

Granzyme

10.1073/pnas.85.13.4814

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Citations (92)

Antibody-independent activation of the complement system by mitochondria is mediated by cardiolipin

Biochemical Journal (1988)

Manuel C. Peitsch J Tschopp A Kress H. Isliker

Non-immune activation of the first component of complement (C1) by the heart mitochondrial inner membrane has been investigated. Cardiolipin, the only strong activator of C1 among phospholipids, is present in large amounts in the heart mitochondrial inner membrane. We therefore studied its contribution to C1 activation by mitochondria. The proteins of the mitochondrial inner membrane were found to activate C1 only weakly, in contrast with the phospholipid fraction which induces strong C1 activation. Furthermore, the digestion of mitochondrial inner membranes with proteolytic enzymes did not affect C1 activation. Additional support in favour of cardiolipin being the responsible activator came from competition experiments with mitochondrial creatine kinase (mt-CPK) and adriamycin, known to bind to cardiolipin. Both mt-CPK and adriamycin displaced C1q from the mitochondrial inner membrane. In addition, C1q displaced mt-CPK bound to mitoplasts.

Inner membrane

Mitochondrial carrier

10.1042/bj2490495

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Citations (45)

Fas ligand expression is restricted to nonlymphoid thymic components in situ.

The Journal of Immunology (1997)

Lars E. French A Wilson Michael Hahne I. Viard J Tschopp

The cell surface receptor Fas (Apo-1/CD95) and its ligand (FasL) are mediators of apoptosis that have been shown to be implicated in activation-induced death of mature T cells and in killing mediated by cytolytic T cells. The role of the Fas pathway in apoptosis associated with thymic selection events is, however, controversial. Although Fas and FasL are known to be expressed in the thymus, the nature and in vivo localization of FasL-expressing cells have not been determined. Using recently developed anti-FasL Abs in combination with in situ hybridization on tissue sections, we show in this work that FasL-expressing cells are present in the thymus, particularly within the medulla. FasL mRNA was detected readily in thymic stromal cell extracts, but not in isolated thymocytes. Moreover, immunohistochemical analysis of serial tissue sections stained with Abs against FasL in conjunction with epithelial and dendritic cell markers indicated that both thymic epithelial and dendritic cells express FasL in situ. The coexistence of FasL-expressing stromal cells and Fas-expressing thymocytes may have important implications for the role of the Fas pathway in apoptosis associated with thymic selection events.

Fas ligand

10.4049/jimmunol.159.5.2196

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Citations (51)

Effects of purified perforin and granzyme A from cytotoxic T lymphocytes on guinea pig ventricular myocytes

Cardiovascular Research (1994)

Bella Felzen Gideon Berke D Rosen Raymond Coleman J Tschopp

Objective: Involvement of cytotoxic T lymphocytes (CTL) in heart transplant rejection as well as in viral myocarditis is well established, but the precise mechanisms whereby infiltrating CTL damage the myocardium are unknown. The aim of the study was to investigate how CTL derived perforin, the serine protease granzyme A, and the combination of both, damage guinea pig ventricular myocytes. Methods: Action potentials and membrane currents were recorded by means of the whole cell configuration from guinea pig ventricular myocytes. Results: Resembling the effects of CTL derived lytic granules, perforin caused gradual myocyte shortening and contracture, leading to complete loss of the rod shaped morphology and to cell destruction. These changes were preceded by shortening of action potential duration and reduction of resting potential and action potential amplitude, followed by complete inexcitability. Granzyme A alone was ineffective, but accelerated the deleterious effects of perforin on the morphological and electrophysiological properties of myocytes. The effects of perforin were further evaluated by measuring membrane currents by means of the whole cell voltage clamp. Perforin induced discrete changes in membrane current, reminiscent of single ion channels, with large conductance and open time of up to several seconds. Linear regression analysis of the channel I-V relations resulted in a conductance of 890 pS and a reversal potential of −7.6 mV. These results suggest that perforin induces large non-selective channels, which can account for most of the observed adverse effects. Conclusions: As CTL participate in the immunological rejection of the transplanted heart, it is conceivable, but remains to be shown, that part of this damage is inflicted by perforin containing lytic granules. Cardiovascular Research 1994;28:643-649

Granzyme A

Granzyme

CTL*

10.1093/cvr/28.5.643

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Citations (18)

Clusterin, the human apolipoprotein and complement inhibitor, binds to complement C7, C8 beta, and the b domain of C9.

The Journal of Immunology (1993)

J Tschopp Arcadio Chonn Sylvie Hertig Lars E. French

Clusterin is a heterodimeric multifunctional protein expressed in a variety of tissues and cells. It forms high density lipid complexes in plasma and participates in the control of the lytic activity of the late complement complex (TCC, C5b-9). Together with vitronectin, clusterin binds to the nascent amphiphilic C5b-9 complex, rendering it water soluble and lytically inactive. To define the interactions that underlie the complement-inhibitory function of clusterin, we have examined the binding interactions between [125I]clusterin and the isolated components of the complex, C5b-6, C7, C8, and C9 and vitronectin. By using ligand blotting in the presence of Tween, specific binding of the labeled clusterin with C7, the beta-subunit of C8 and C9 was detected. Binding to C9 was competed by polymerized C9, but not by C8, C7, C6, and CD59, suggesting that the conformational change occurring during the hydrophilic-amphiphilic transition of C9 exposes the interaction site for clusterin. When thrombin-treated C9 was analyzed, clusterin was found to recognize the C9b fragment containing the hydrophobic membrane interaction segment. Both subunits of clusterin interact with C9 and are similarly potent in inhibiting C5b-9-mediated hemolysis and Zn+(+)-induced C9 polymerization. These results show that clusterin exerts its inhibitory effect by interacting with a structural motif common to C7, C8 alpha, and C9b.

Clusterin

CD59

Anaphylatoxin

10.4049/jimmunol.151.4.2159

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Citations (178)

Antibody-independent activation of C1, the first component of complement, by cardiolipin.

The Journal of Immunology (1985)

Tibor Kovacsovics J Tschopp A Kress H. Isliker

Lipid vesicles containing phospholipids known to be present in substantial amounts in mitochondrial membranes were tested for their capacity to activate C1. Among them, only cardiolipin (CL) was highly efficient in C1 activation; no such effect was observed with phosphatidylcholine, phosphatidylethanolamine, or phosphatidylinositol. CL was shown to bind specifically C1q, because only unlabeled C1q competed with 125I-C1q for binding to CL. The requirement for C1q was confirmed by the finding that only fully reconstituted macromolecular C1, containing C1q, was activated by CL. The specificity of CL-induced activation of C1 was also demonstrated by introducing adriamycin, an agent known to interact with CL. Whereas adriamycin did not decrease C1 activation induced by immune complexes, it abrogated C1 activation by CL. The latter was shown to be a strong nonimmune activator of C1, because C1-INH did not inhibit CL-induced activation. When the concentration of CL in vesicles was decreased in the presence of phosphatidylcholine, C1 activation was detected only above a critical level of 35 mol% CL, compatible with a minimal density or clustering of CL molecules in the plane of the membrane. Moreover, C1 activation by CL was modulated by the addition of cholesterol. The threshold of CL required for C1 activation was lowered by the incorporation of more than 35 mol% cholesterol into the vesicles. These results show that CL incorporated into liposomes can be a potent nonimmune activator of C1. The negatively charged phosphate groups in CL are likely candidates for Clq-binding.

Phosphatidylethanolamine

10.4049/jimmunol.135.4.2695

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Citations (74)

Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-x_L

Proceedings of the National Academy of Sciences (1999)

David C.S. Huang Michael Hahne Michael Schroeter Karl Frei A. Fontana

Fas activation triggers apoptosis in many cell types. Studies with anti-Fas antibodies have produced conflicting results on Fas signaling, particularly the role of the Bcl-2 family in this process. Comparison between physiological ligand and anti-Fas antibodies revealed that only extensive Fas aggregation, by membrane bound FasL or aggregated soluble FasL consistently triggered apoptosis, whereas antibodies could act as death agonists or antagonists. Studies on Fas signaling in cell lines and primary cells from transgenic mice revealed that FADD/MORT1 and caspase-8 were required for apoptosis. In contrast, Bcl-2 or Bcl-x L did not block FasL-induced apoptosis in lymphocytes or hepatocytes, demonstrating that signaling for cell death induced by Fas and the pathways to apoptosis regulated by the Bcl-2 family are distinct.

Fas ligand

FADD

Caspase 8

10.1073/pnas.96.26.14871

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Citations (295)

Design & synthesis of novel cyclic rgd peptides as highly potent & selective GPIIb/IIIa antagonists

Peptides (1994)

Shan Cheng W. S. Craig D. Mullen J Tschopp Douglas B. Dixon

10.1007/978-94-011-0683-2_124

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Citations (1)

Isolation and complete structure of the lymphocyte serine protease granzyme G, a novel member of the granzyme multigene family in murine cytolytic T lymphocytes. Evolutionary origin of lymphocyte proteases

Biochemistry (1989)

Dieter E. Jenne Danièle Masson Michael Zimmer Jacques‐Antoine Haefliger Wen‐Hsiung Li

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIsolation and complete structure of the lymphocyte serine protease granzyme G, a novel member of the granzyme multigene family in murine cytolytic T lymphocytes. Evolutionary origin of lymphocyte proteasesDieter E. Jenne, Daniele Masson, Michael Zimmer, Jacques Antoine Haefliger, Wen Hsiung Li, and Juerg TschoppCite this: Biochemistry 1989, 28, 19, 7953–7961Publication Date (Print):September 19, 1989Publication History Published online1 May 2002Published inissue 19 September 1989https://pubs.acs.org/doi/10.1021/bi00445a060https://doi.org/10.1021/bi00445a060research-articleACS PublicationsRequest reuse permissionsArticle Views60Altmetric-Citations45LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

Granzyme

Granzyme A

CTL*

10.1021/bi00445a060

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Citations (56)

Is Fas ligand (CD95L) expression by astrocytoma cells a major mechanism of inactivation of tumour infiltrating lymphocytes?

Immunology Letters (1997)

Philippe Saas Paul R. Walker Michael Hahne Anne‐Lise Quiquerez Valérie Schnüriger

Fas ligand

10.1016/s0165-2478(97)86766-1

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