Teilprojekt 2
Caspase-1 (IL-1β converting enzyme, ICE), ein proinflammatorisches Enzym, spielt bei der Pathogenese autoinflammatorischer Erkrankungen eine bedeutende Rolle. Nach Phagozyten-aktivierung erfolgt die Integration von Pro-Caspase-1 in Inflammasome sowie die Umwandlung in die aktive Caspase-1, welche durch proteolytische Spaltung die Reifung von IL-1β bewirkt. Unabhängig von der enzymatischen Aktivität ist Pro-Caspase-1 in der Lage, über die CARD Domäne mit anderen CARD-tragenden Proteinen zu interagieren. Ein Interaktionspartner ist RIP2 (receptor interacting protein 2). Die CARD-Caspase1-CARD-RIP2-Interaktion führt zur Aktivierung von NF-kB und somit weiterer proinflammatorischer Signalwege.
Ziel dieses Projekts ist es, die Auswirkungen von CASP1-Mutationen auf die subzelluläre Lokalisation der Pro-Caspase-1 und deren Bindungspartner RIP2 und ASC sowie auf die Heterodimerbildung und die Interaktion mit RIP2 mittels Fluoreszenzkreuzkorrelationsspektroskopie detailliert in vitro und in vivo zu untersuchen. Die erwarteten Ergebnisse sollen zu einem besseren Verständnis der Pathogenese von Autoinflammation beitragen.
Teilprojektleiter
Prof. Dr. med. Sigrun R. Hofmann
Klinik und Poliklinik für Kinder- und Jugendmedizin
Universitätsklinikum Carl Gustav Caru
Mitarbeiter
Susanne Russ, MTA
Tel.: 0351-458 6883
Email: susanne.russ
Ausgewählte Publikationen
Hofmann SR, Schnabel A, Rösen-Wolff A, Morbach H, Girschick HJ, Hedrich CM. Chronic Nonbacterial Osteomyelitis: Pathophysiological Concepts and Current Treatment Strategies. J Rheumatol. 2016 Nov;43(11):1956-1964.
Stein R, Kapplusch F, Heymann MC, Russ S, Staroske W, Hedrich CM, Rösen-Wolff A, Hofmann SR. Enzymatically Inactive Procaspase 1 stabilizes the ASC Pyroptosome and Supports Pyroptosome Spreading during Cell Division. J Biol Chem. 2016 Aug 26;291(35):18419-29.
Hofmann SR, Kubasch AS, Range U, Laass MW, Morbach H, Girschick HJ, Hedrich CM. Serum biomarkers for the diagnosis and monitoring of chronic recurrent multifocal osteomyelitis (CRMO). Rheumatol Int. 2016 Jun;36(6):769-79.
Hedrich CM, Hofmann SR, Pablik J, Morbach H, Girschick HJ. Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO). Pediatr Rheumatol Online J. 2013 Dec 23;11(1):47.
Heymann MC, Rabe S, Ruß S, Kapplusch F, Schulze F, Stein R, Winkler S, Hedrich CM, Rösen-Wolff A, Hofmann SR. Fluorescent tags influence the enzymatic activity and subcellular localization of procaspase-1. 2015 Oct;160(2):172-9.
Luksch H, Winkler S, Heymann MC, Schulze F, Hofmann SR, Roesler J, Rösen-Wolff A. Current knowledge on procaspase-1 variants with reduced or abrogated enzymatic activity in autoinflammatory disease. Curr Rheumatol Rep. 2015;17(7):520-527.
Heymann MC, Winkler S, Luksch H, Flecks S, Ritter L, Franke M, Ruß S, Özen S, Yilmaz E, Klein C, Kallinich T, Lindemann D, Brenner S, Ganser G, Roesler J, Rösen-Wolff A, Hofmann SR. Human procaspase-1 variants with decreased enzymatic activity are associated with febrile episodes and may contribute to inflammation via RIP2 and NFkB signaling. J Immunol. 2014 May 1;192(9):4379-85.
Heymann M, Winkler S, Özen S, Yilmaz E, Kallinich T, Rösen-Wolff A, Roesler J, Hofmann S (2013). Procaspase-1 contributes to inflammation via NF-KB. Pediatric Rheumatology 11(Suppl 1):A251.
Rabe S, Heymann MC, Russ S, Winkler S, Roesler J, Rösen-Wolff A, Hofmann SR (2013). CASP1 variants and live cell imaging. Pediatric Rheumatology 11(Suppl 1):A253.
Luksch H, Romanowski MJ, Chara O, Tüngler V, Caffarena ER, Heymann MC, Lohse P, Aksentijevich I, Remmers EF, Flecks S, Quoos N, Gramatté J, Petzold C, Hofmann SR, Winkler S, Pessler F, Kallinich T, Ganser G, Nimtz-Talaska A, Baumann U, Runde V, Grimbacher B, Birmelin J, Gahr M, Roesler J, Rösen-Wolff A. Naturally occurring genetic variants of human caspase-1 differ considerably in structure and the ability to activate interleukin-1β. Hum Mutat 2013;34(1):122-31.
Hofmann SR, Heilmann A, Häusler HJ, Kamin G, Nitzsche KI. Agenesis of the ductus venosus-A case with favorable outcome after early signs of cardiac failure. J Clin Ultrasound. 2013 Mar-Apr;41(3):187-90.
Heymann MC, Rösen-Wolff A. Contribution of the inflammasomes to autoinflammatory diseases and recent mouse models as research tools. Clin Immunol 2013. 2013 Jun;147(3):175-84.
Winkler S, Heymann MC, Franke M, Martin A, Roesler J, Rösen-Wolff A. Shock 2012;37(6):659.
Hofmann SR, Morbach H, Schwarz T, Rösen-Wolff A, Girschick HJ, Hedrich CM. Attenuated TLR4/MAPK signaling in monocytes from patients with CRMO results in impaired IL-10 expression. Clin Immunol 2012;145(1):69-76.
Hofmann SR, Roesen-Wolff A, Hahn G, Hedrich CM. Update: Cytokine Dysregulation in Chronic Nonbacterial Osteomyelitis (CNO). Int J Rheumatol 2012; 2012:310206.
Hofmann SR, Rösen-Wolff A, Tsokos GC, Hedrich CM. Biological properties and regulation of IL-10 related cytokines and their contribution to autoimmune disease and tissue injury. Clin Immunol 2012;143(2):116-27.
Hofmann SR, Möller J, Rauen T, Paul D, Gahr M, Rösen-Wolff A, Brenner S, Hedrich CM. Dynamic CpG-DNA methylation of Il10 and Il19 in CD4+ T lymphocytes and macrophages: effects on tissue-specific gene expression. Klin Padiatr 2012;224(2):53-60.
Heymann MC, Hofmann SR. Novel Inflammasomes and Type II Diabetes, Intestinal Inflammation and Psoriasis as newly Inflammasome-related Diseases. J Genet Syndr Gene Ther 2011. dx.doi.org/10.4172/2157-7412.53-001.
Hofmann SR, Heymann MC, Hermsdorf A, Rösen-Wolff A. Recent Advances in Autoinflammatory Diseases and Animal Models. J Genet Syndr Gene Ther 2011. dx.doi.org/10.4172/2157-7412.S3-002.
Hofmann SR, Schwarz T, Möller JC, Morbach H, Schnabel A, Rösen-Wolff A, Girschick HJ, Hedrich CM. Chronic non-bacterial osteomyelitis is associated with impaired Sp1 signaling, reduced IL10 promoter phosphorylation, and reduced myeloid IL-10 expression. Clin Immunol 2011;141(3):317-27.
Watford WT, Li D, Agnello D, Durant L, Yamaoka K, Yao ZJ, Ahn HJ, Cheng TP, Hofmann SR, Cogliati T, Chen A, Hissong BD, Husa MR, Schwartzberg P, O’Shea JJ, Gadina M. Cytohesin binder and regulator (Cybr) is not essential for T- and dendritic-cell activation and differentiation. Mol Cell Biol 2006;26(17):6623-32.
Pesu M, Candotti F, Husa M, Hofmann SR, Notarangelo LD, O’Shea JJ. Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs. Immunol Rev 2005;203:127-142.
Hofmann SR, Lam AQ, Frank S, Zhou YJ, Ramos HL, Kanno Y, Agnello D, Youle RJ, O’Shea JJ. Jak3-independent trafficking of the common gamma chain receptor subunit: chaperone function of Jaks revisited. Mol Cell Biol 2004;24(11):5039-49.
O’Shea JJ, Husa M, Li D, Hofmann SR, Watford WT, Roberts J, Buckley R, Changelian P, Candotti F. Jak3 and the pathogenesis of severe combined immunodeficiency. Mol Immunol 2004;41:727-37.
Hofmann SR, Aringer M, Frucht DM, Chen M, Centola M, Morinobu A, Visconti R, Kastner DL, Smolen JS, O'Shea JJ. Characterization and analysis of the proximal Janus Kinase 3 promoter. J Immunol 2003;170(12):6057-64.
Nguyen KB, Watford WT, Salomon R, Hofmann SR, Pien GC, Morinobu A, Gadina M, O'Shea JJ, Biron CA. Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection. Science 297 2002;(5589):2063-6.
Hofmann SR, Ettinger R, Zhou YJ, Gadina M, Lipsky P, Siegel R, Candotti F, O'Shea JJ. Cytokines and their role in lymphoid development, differentiation and homeostasis. Curr Opin Allergy Clin Immunol 2002;2(6):495-506.
Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, Stein L, Russo R, Goldsmith D, Dent P, Rosenberg HF, Austin F, Remmers EF, Balow JE Jr, Rosenzweig S, Komarow H, Shoham NG, Wood G, Jones J, Mangra N, Carrero H, Adams BS, Moore TL, Schikler K, Hoffman H, Lovell DJ, Lipnick R, Barron K, O'Shea JJ, Kastner DL, Goldbach-Mansky R. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum 2002;46(12):3340-8.