Tschopp Jürg

The Director, Professors and all members of the Department of Biochemistry have profound regret in announcing the sudden and tragic loss of our colleague, Professor Jürg Tschopp, who passed away on Tuesday March 22, 2011.

Throughout his career, Jürg Tschopp has demonstrated a long-standing interest in cell death, the mechanisms of danger detection and the ensuing repair or killing processes. This curiosity was fostered during his post-doctoral work where he investigated the mechanism of lysis induced by complement. He discovered that the complement pore is formed by multimers of complement C9 (Tschopp et al., 1982). After his return to Switzerland, he unraveled the cytolytic machinery that is used by cytolytic T cells to kill tumor or virally infected cells. He characterized cytoplasmic granules within cytolytic T cells (CTLs) and discovered perforin, the major lytic protein, and a family of proteases, the so-called granzymes (Lowin et al., 1994; Masson and Tschopp, 1987). It is now well established that granzymes, together with perforin, are the two proteins required for efficient target cell death. He next became interested in the role of perforin in vivo. To this end his group generated perforin-deficient mice, which, in 1995, was quite an endeavor. Analysis of these mice revealed a second lytic pathway utilized by CTLs (Lowin et al., 1994). This alternative pathway was dependent on Fas, a now well-known death receptor and potent inducer of apoptosis. This discovery turned his interest to apoptosis. He identified a number of proteins that control apoptosis, amongst which the most powerful inhibitor of the Fas signaling pathway, i.e. FLIP (Irmler et al., 1997) (Thome et al., 1997). Using a bioinformatics approach, Jurg Tschopp discovered several additional Fas and Fas ligand (FasL)-related proteins, for example TRAIL-R, TRAMP, APRIL and BAFF.

BAFF inhibits B cell death and is absolutely essential for B-cell maturation and survival (Schneider et al., 1999). The use of BAFF antagonists is currently been considered for the treatment of autoimmune diseases. Jurg Tschopp also developed a highly potent, proapoptotic form of FasL, which is currently being evaluated for its use as a potential anticancer drug.

In addition to apoptosis, there exists a second type of cell death, necrosis. Necrosis was considered to be a form of accidental death that was independent of a defined signal pathway. Tschopp’s group was the first to discover that like apoptosis, necrosis was precisely controlled by defined signaling pathways and was dependent on the kinase RIP1 (Holler et al., 2000).

Caspases are not only key molecules in the apoptotic process, but some control DNA repair. Tschopp identified another caspase-activating platform which he designated the PIDDosome. This complex assembles upon DNA stress. The PIDDosome has multiple important functions, including the activation of caspase-2 and the orchestration of NF-κB activation and DNA repair mechanisms (Janssens et al., 2005; Tinel and Tschopp, 2004).

Jurg Tschopp also described a novel cytoplasmic protein complex that detects RNA and which is essential for sensing most intracellular viruses. This complex consists of RIG-I and Cardif and triggers a robust type I interferon response. His group could demonstrate that CARDIF is proteolytically inactivated by HCV, thereby explaining the persistency of this virus (Meylan et al., 2005).

In 2002, Jurg Tschopp identified the multprotein complex that activates caspases 1 and 5, which he called inflammasome (Martinon et al., 2002). The clinical implications of this seminal discovery is becoming perceptible only today. Together with other groups, Jurg Tschopp found that mutations in one of the proteins forming the inflammasome are the cause of several autoinflammatory diseases (the CAPS). Based on this discovery, patients suffering from these genetic diseases are now successfully treated with IL-1 antagonists. Recently, Tschopp’s group as well as many other labs identified the role of inflammasome in many different inflammatory conditions (Schroder et al. 2010) including for example gout (Martinon et al., 2006). Again, gout patients can now be successfully treated with IL-1 inhibitors (So et al., 2007).

References

1. Holler, N., Zaru, R., Micheau, O., Thome, M., Attinger, A., Valitutti, S., Bodmer, J.L., Schneider, P., Seed, B., and Tschopp, J. (2000). Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 1, 489-495.
2. Irmler, M., Thome, M., Hahne, M., Schneider, P., Hofmann, K., Steiner, V., Bodmer, J.L., Schroter, M., Burns, K., Mattmann, C., et al. (1997). Inhibition of death receptor signals by cellular FLIP. Nature 388, 190-195.
3. Janssens, S., Tinel, A., Lippens, S., and Tschopp, J. (2005). PIDD mediates NF-kappaB activation in response to DNA damage. Cell 123, 1079-1092.
4. Lowin, B., Hahne, M., Mattmann, C., and Tschopp, J. (1994). Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 370, 650-652.
5. Martinon, F., Burns, K., and Tschopp, J. (2002). The Inflammasome. A Molecular Platform Triggering Activation of Inflammatory Caspases and Processing of proIL-beta. Mol Cell 10, 417.
6. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A., and Tschopp, J. (2006). Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237-241.
7. Masson, D., and Tschopp, J. (1987). A family of serine esterases in lytic granules of cytolytic T lymphocytes. Cell 49, 679-685.
8. Meylan, E., Curran, J., Hofmann, K., Moradpour, D., Binder, M., Bartenschlager, R., and Tschopp, J. (2005). Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167-1172.
9. Schneider, P., MacKay, F., Steiner, V., Hofmann, K., Bodmer, J.L., Holler, N., Ambrose, C., Lawton, P., Bixler, S., Acha-Orbea, H., et al. (1999). BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 189, 1747-1756.
10. Schroder K, Zhou R, Tschopp J. (2010) The NLRP3 inflammasome: a sensor for metabolic danger? Science 5963 296-300
11. So, A., De Smedt, T., Revaz, S., and Tschopp, J. (2007). A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 9, R28.
12. Thome, M., Schneider, P., Hofmann, K., Fickenscher, H., Meinl, E., Neipel, F., Mattmann, C., Burns, K., Bodmer, J.L., Schroter, M., et al. (1997). Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386, 517-521.
13. Tinel, A., and Tschopp, J. (2004). The PIDDosome, a Protein Complex Implicated in Activation of Caspase-2 in Response to Genotoxic Stress. Science 304, 843-846.
14. Tschopp, J., Muller-Eberhard, H.J., and Podack, E.R. (1982). Formation of transmembrane tubules by spontaneous polymerization of the hydrophilic complement protein C9. Nature 298, 534-538.

Dixit V. Jürg Tschopp (1951-2011). Nature 2011; 472:256.

O'Neill LA. Retrospective. Jürg Tschopp (1951-2011). Science 2011; 6030:679.

Flavell RA. Jürg Tschopp 1951-2011. Cell 2011; 145:493–4 and Mol Cell 2011; 42:551–2.

Budd RC, Schneider P, Mackay F, Strasser A. Jürg Tschopp 1951–2011. Nat Immunol 2011; 12:367–7.

Browning J, Ware C. Jürg Tschopp. Immunity 2011; 34:451–2.

Romero P. Professor Jürg Tschopp (1951-2011). Eur. J. Immunol. 2011; 41: 1189-90.

Wallach D. Jürg Tschopp. Cytokine 2011; 54:233–4.

Kroemer G, Martinon F, Lippens S, Green DR, Knight R, Vandenabeele P, Piacentini M, Nagata S, Borner C, Simon H-U, Krammer P, Melino G. Jürg Tschopp—1951–2011—an immortal contribution. Cell Death Differ 2011; 18: 1087–88.

Special Issue cell death and differentiation (12 articles) 

• Drexler SK, Bonsignore L, Masin M, Tardivel A, Jackstadt R, Hermeking H, Schneider P, Gross O, Tschopp J, Yazdi AS. (2012). Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis. Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18384-9. doi: 10.1073/pnas.1209171109. Epub 2012 Oct 22. PubMed
• Chow MT, Sceneay J, Paget C, Wong CS, Duret H, Tschopp J, Möller A, Smyth MJ. (2012). NLRP3 Suppresses NK Cell-Mediated Responses to Carcinogen-Induced Tumors and Metastases. Cancer Res. 2012 Nov 15;72(22):5721-32. doi: 10.1158/0008-5472.CAN-12-0509. Epub 2012 Sep 17. PubMed
• Chow MT, Tschopp J, Möller A, Smyth MJ. (2012). NLRP3 promotes inflammation-induced skin cancer but is dispensable for asbestos-induced mesothelioma. Immunol Cell Biol. 2012 Nov;90(10):983-6. doi: 10.1038/icb.2012.46. Epub 2012 Sep 25. PubMed
• Ando K, Kernan JL, Liu PH, Sanda T, Logette E, Tschopp J, Look AT, Wang J, Bouchier-Hayes L, Sidi S. (2012). PIDD death-domain phosphorylation by ATM controls prodeath versus prosurvival PIDDosome signaling. Mol Cell. 2012 Sep 14;47(5):681-93. doi: 10.1016/j.molcel.2012.06.024. Epub 2012 Jul 30. PubMed
• Groß O, Yazdi AS, Thomas CJ, Masin M, Heinz LX, Guarda G, Quadroni M, Drexler SK, Tschopp J. (2012) Inflammasome Activators Induce Interleukin-1α Secretion via Distinct Pathways with Differential Requirement for the Protease Function of Caspase-1. Immunity. 2012 Mar 23;36(3):388-400. PubMed
• Staehli F, Ludigs K, Heinz LX, Seguín-Estévez Q, Ferrero I, Braun M, Schroder K, Rebsamen M, Tardivel A, Mattmann C, Macdonald HR, Romero P, Reith W, Guarda G, Tschopp J. (2012) NLRC5 Deficiency Selectively Impairs MHC Class I- Dependent Lymphocyte Killing by Cytotoxic T Cells. J Immunol. 2012 Apr 15;188(8):3820-8. Epub 2012 Mar 12. PubMed
• Erener S, Pétrilli V, Kassner I, Minotti R, Castillo R, Santoro R, Hassa PO, Tschopp J, Hottiger MO. (2012) Inflammasome-Activated Caspase 7 Cleaves PARP1 to Enhance the Expression of a Subset of NF-κB Target Genes. Mol Cell. 2012 Mar 28. [Epub ahead of print] PubMed
• Gross, O. (2012). Measuring the inflammasome. Methods Mol Biol. 2012;844:199-222. doi: 10.1007/978-1-61779-527-5_15. PubMed
• Vince JE, Wong WW, Gentle I, Lawlor KE, Allam R, O'Reilly L, Mason K, Gross O, Ma S, Guarda G, Anderton H, Castillo R, Häcker G, Silke J, Tschopp J. (2012) Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity. 2012 Feb 24;36(2):215-27. PubMed
• Menu P, Mayor A, Zhou R, Tardivel A, Ichijo I, Mori K, Tschopp J. (2012) ER stress activates the NLRP3 inflammasome via an UPR-independent pathway. Cell Death Dis. 2012 Jan 26;3:e261. doi: 10.1038/cddis.2011.132. PubMed
• Heinz LX, Rebsamen M, Rossi DC, Staehli F, Schroder K, Quadroni M, Gross O, Schneider P, Tschopp J. (2012) The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade. Cell Death Differ. 2012 Apr;19(4):722-31. doi: 10.1038/cdd.2011.147. Epub 2011 Dec 9. PubMed
• Kupz A, Guarda G, Gebhardt T, Sander LE, Short KR, Diavatopoulos DA, Wijburg OL, Cao H, Waithman JC, Chen W, Fernandez-Ruiz D, Whitney PG, Heath WR, Curtiss R 3rd, Tschopp J, Strugnell RA, Bedoui S. (2012) NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8⁺ T cells. Nat Immunol. 2012 Jan 8;13(2):162-9. doi: 10.1038/ni.2195. PubMed
• Dorhoi A, Nouailles G, Jörg S, Hagens K, Heinemann E, Pradl L, Oberbeck-Müller D, Duque-Correa MA, Reece ST, Ruland J, Brosch R, Tschopp J, Gross O, Kaufmann SH. (2012) Activation of the NLRP3 inflammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis. Eur J Immunol. 2012 Feb;42(2):374-84. doi: 10.1002/eji.201141548. Epub 2011 Dec 20. PubMed
• Gross O, Thomas CJ, Layland LE (2011). Inflammasome activation in response to eukaryotic pathogens. In: The Inflammasomes (I. Couillin, V. Pétrilli, F. Martinon, Eds) Springer.
• Gross O, Thomas CJ, Guarda G, Tschopp, J. (2011). The inflammasome: an integrated view. Immunol Rev., 243, 136-151. PubMed
• Witzenrath M, Pache F, Lorenz D, Koppe U, Gutbier B, Tabeling C, Reppe K, Meixenberger K, Dorhoi A, Ma J, Holmes A, Trendelenburg G, Heimesaat MM, Bereswill S, van der Linden M, Tschopp J, Mitchell TJ, Suttorp N, Opitz B. (2011). The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia. J Immunol., 187, 434-440. PubMed
• Rebsamen M, Vazquez J, Tardivel A, Guarda G, Curran J, Tschopp J. (2011). NLRX1/NOD5 deficiency does not affect MAVS signalling. Cell Death Differ., 18, 1387. PubMed
• Tschopp J. (2011). Mitochondria: Sovereign of inflammation? Eur J Immunol., 41,1196-202. PubMed
• Mankan AK, Canli O, Schwitalla S, Ziegler P, Tschopp J, Korn T, Greten FR (2011). TNF-alpha-dependent loss of IKKbeta-deficient myeloid progenitors triggers a cytokine loop culminating in granulocytosis. Proc Natl Acad Sci USA. 108, 6567-6572. PubMed
• Menu P, Pellegrin M, Aubert JF, Bouzourene K, Tardivel A, Mazzolai L, Tschopp J (2011). Atherosclerosis in ApoE-deficient mice progresses independently of the NLRP3 inflammasome. Cell Death Dis., 2, e137. PubMed
• Besnard AG, Guillou N, Tschopp J, Erard F, Couillin I, Iwakura Y, Quesniaux V, Ryffel B, Togbe D (2011). NLRP3 inflammasome is required in murine asthma in the absence of aluminum adjuvant. Allergy, 66, 1047-1057. PubMed
• Logette E, Schuepbach-Mallepell S, Eckert MJ, Leo XH, Jaccard B, Manzl C, Tardivel A, Villunger A, Quadroni M, Gaide O, Tschopp J. (2011). PIDD orchestrates translesion DNA synthesis in response to UV irradiation. Cell Death Differ. 18, 1036-1045. PubMed
• Flach TL, Ng G, Hari A, Desrosiers MD, Zhang P, Ward SM, Seamone ME, Vilaysane A, Mucsi AD, Fong Y, Prenner E, Ling CC, Tschopp J, Muruve DA, Amrein MW, Shi Y (2011). Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nat Med. 17, 479-87. PubMed
• Guarda G, Braun M, Staehli F, Tardivel A, Mattmann C, Förster I, Farlik M, Decker T, Du Pasquier RA, Romero P, Tschopp J. (2011). Type I interferon inhibits interleukin-1 production and inflammasome activation. Immunity, 34, 213-23. PubMed
• Allam R, Darisipudi MN, Rupanagudi KV, Lichtnekert J, Tschopp J, Anders HJ (2011). Cyclic polypeptide and aminoglycoside antibiotics trigger IL-1β secretion by activating the NLRP3 inflammasome. J Immunol., 186, 2714-2718. PubMed
• Guarda G, Zenger M, Yazdi AS, Schroder K, Ferrero I, Menu P, Tardivel A, Mattmann C, Tschopp J. (2011). Differential expression of NLRP3 among hematopoietic cells. J Immunol., 186, 2529-2534. PubMed
• Harris J, Hartman M, Roche C, Zeng SG, O'Shea A, Sharp FA, Lambe EM, Creagh EM, Golenbock DT, Tschopp J, Kornfeld H, Fitzgerald KA, Lavelle EC (2011). Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J Biol Chem. 286, 9587-9597. PubMed
• Zhou R, Yazdi AS, Menu P, Tschopp J. (2011). A role for mitochondria in NLRP3 inflammasome activation. Nature, 469, 221-225. Erratum in: Nature, 475, 122, 2011. PubMed
• Tinel A, Eckert MJ, Logette E, Lippens S, Janssens S, Jaccard B, Quadroni M, Tschopp J. (2011). Regulation of PIDD auto-proteolysis and activity by the molecular chaperone Hsp90. Cell Death Differ., 18, 506-515. PubMed
• Hirota SA, Ng J, Lueng A, Khajah M, Parhar K, Li Y, Lam V, Potentier MS, Ng K, Bawa M, McCafferty DM, Rioux KP, Ghosh S, Xavier RJ, Colgan SP, Tschopp J, Muruve D, MacDonald JA, Beck PL (2011). NLRP3 inflammasome plays a key role in the regulation of intestinal homeostasis. Inflamm Bowel Dis., 17, 1359-1372. PubMed
• Yazdi AS, Guarda G, Riteau N, Drexler SK, Tardivel A, Couillin I, Tschopp J. (2010). Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1α and IL-1β. Proc Natl Acad Sci USA. 107, 19449-19454. PubMed
• Schroder K, Tschopp J. (2010). The inflammasomes. Cell 140, 821-832. PubMed
• Schroder K, Zhou R, Tschopp J. (2010). The NLRP3 inflammasome: a sensor for metabolic danger? Science 327, 296-300. PubMed
• Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. (2010). Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 11, 136-140. PubMed
• Guarda G, Dostert C, Staehli F, Cabalzar K, Castillo R, Tardivel A, Schneider P, Tschopp J. (2009). T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes. Nature 460, 269-273. PubMed
• Rebsamen M, Heinz LX, Meylan E, Michallet MC, Schroder K, Hofmann K, Vazquez J, Benedict CA, Tschopp J. (2009). DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB. EMBO Rep. 10, 916-922. PubMed
• Rebsamen M, Meylan E, Curran J, Tschopp J. (2008b). The antiviral adaptor proteins Cardif and Trif are processed and inactivated by caspases. Cell Death Differ. 15, 1804-11. PubMed
• Dostert C, Pétrilli V, Van Bruggen R, Steele C, Mossman B, Tschopp J. (2008c). Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674-7. PubMed
• Dostert C, Meylan E, Tschopp J. (2008a). Intracellular pattern-recognition receptors. Adv Drug Deliv Rev. 60, 830-40. PubMed
• Cuenin S, Tinel A, Janssens S, Tschopp J. (2008a). p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress. Oncogene 27, 387-96. PubMed
• Muruve DA, Petrilli V, Zaiss AK, White LR, Clark SA, Ross J, Park, RA, Tschopp J. (2008). The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature, 452, 103-107. PubMed
• Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. (2008). Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674-677. PubMed
• Michallet MC, Meylan E, Ermolaeva MA, Vazquez J, Rebsamen M, Curran J, Poeck H, Bscheider M, Hartmann G, Konig M, et al. (2008). TRADD protein is an essential component of the RIG-like helicase antiviral pathway. Immunity 28, 651-661. PubMed