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Project 15
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Project 15

Manolis Pasparakis

Innate receptor signalling in host defence

Institute for Genetics, University of Cologne


Brief description in German:
Die angeborene Immunität basiert auf der Erkennung mikrobieller Produkte durch sogenannte Pattern recognition receptors, die durch intrazelluläre Signalkaskaden die Expression von Cytokinen und Interferonen zur Koordination antibakterieller und antiviraler Immunantworten induzieren. Aktuelle Forschungsarbeiten aus unserem und anderen Laboren haben gezeigt, dass die PRR initiierten Signalkaskaden Adaptermoleküle wie FADD, TRADD und RIP1 involvieren, die dem TNFR1 Signalweg zugeordnet werden. Durch Anwendung relevanter Mausmodelle soll untersucht werden, wie diese Adaptermoleküle angeborene Immunantworten kontrollieren.

Innate immune responses are essential for cell-autonomous immunity to microbial infections. Innate immunity depends on pathogen detection by pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors and RIG-like helicases (RLHs), which sense bacterial and viral pathogen associated molecular patterns (PAMPs) in the extracellular space, endosomal compartments or in the cytoplasm. PAMP-sensing by PRRs results in the rapid activation of NF-kappaB, mitogen activated protein kinase (MAPK) and interferon regulator factor (IRF) signalling cascades leading to the expression of cytokines and interferons that orchestrate host-defence responses.

Recent studies showed that adapter molecules previously known to regulate TNFR1 signalling are also implicated in PRR signalling. The death domain (DD) containing kinase RIP1 was shown to be important for TRIF-dependent signalling downstream of TLR3 and TLR4, and also for the induction of RIG-like helicase (RLH)-mediated anti-viral interferon responses. Also, the death domain-containing adapter FADD, previously known for its essential function in death receptor-induced apoptosis, was shown to be required for RLH-mediated interferon responses.

More recently, we showed that TRADD has an essential, albeit cell-specific, function not only for TNFR1 but also for TRIF-dependent TLR3 and TLR4 signalling. While these results suggest that FADD, TRADD and RIP1 are central regulators of innate immune responses by nucleating the formation of distinct signalling complexes, the molecular mechanisms by which these proteins control PRR signalling remain elusive.

Here we propose to study the molecular mechanisms by which TRADD, FADD and RIP1 control innate immune receptor signalling using relevant mouse models. We will study the response of physiologically relevant primary cells, (e.g. macrophages, dendritic cells and MEFs) lacking TRADD, FADD, or RIP1 to different PAMPs in order to dissect the function of each of these proteins in signalling downstream of TLRs, NLRs and RLHs. In addition, we will use molecular, biochemical and proteomic approaches to study the molecular mechanisms by which these proteins trigger the activation of NF-kappaB, MAPK and IRF pathways downstream of PRR stimulation.

Ubiquitination has emerged as a critical mechanism for the activation of signalling downstream of cytokine and innate immune receptors. The ability of NEMO/IKKgamma to bind ubiquitin chains is thought to be essential for the activation of NF-kappaB and MAP kinase cascades downstream of TNFR and TLR signalling. Human patients with mutations affecting the C-terminal zinc finger (ZF) domain of NEMO suffer from severe immune deficiency and experience life threatening bacterial infections. Recent evidence indicates that the C-terminal ZF of NEMO is involved in binding K63-linked ubiquitin chains. However the mechanisms by which this domain controls IKK signalling remain poorly understood.

We have generated a mouse model allowing the conditional (Cre/loxP-mediated) replacement of the endogenous wild type NEMO protein with a mutated NEMO lacking the ZF domain. We will use this mouse model to study the mechanisms by which the C-terminal ZF of NEMO regulates signalling downstream of PRRs and cytokine receptors during innate immune responses.


List of publications resulting from the project
Peer-reviewed publications:

Vlantis K, Polykratis A, Welz PS, van Loo G, Pasparakis M, Wullaert A (2015) TLR-independent anti-inflammatory function of intestinal epithelial TRAF6 signalling prevents DSS-induced colitis in mice. Gut, in press

Kim C, Pasparakis M (2014) Epidermal p65/NF-κB signalling is essential for skin carcinogenesis. EMBO Mol Med. 6(7):970-83

Ehlken H, Krishna-Subramanian S, Ochoa-Callejero L, Kondylis V, Nadi NE, Straub BK, Schirmacher P, Walczak H, Kollias G, Pasparakis M (2014) Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout. Cell Death Differ 21(11):1721-32

Polykratis A, Hermance N, Zelic M, Roderick J, Kim C, Van TM, Lee TH, Chan FK, Pasparakis M, Kelliher MA (2014) RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo. J Immunol 193(4):1539-43

Dannappel M, Vlantis K, Kumari S, Polykratis A, Kim C, Wachsmuth L, Eftychi C, Lin J, Corona T, Hermance N, Zelic M, Kirsch P, Basic M, Bleich A, Kelliher M, Pasparakis M (2014) RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513(7516):90-4

Roderick JE, Hermance N, Zelic M, Simmons MJ, Polykratis A, Pasparakis M, Kelliher MA (2014) Hematopoietic RIPK1 deficiency results in bone marrow failure caused by apoptosis and RIPK3-mediated necroptosis. Proc Natl Acad Sci U S A. 111(40):14436-41

Kumari S, Redouane Y, Lopez-Mosqueda J, Shiraishi R, Romanowska M, Lutzmayer S, Kuiper J, Martinez C, Dikic I, Pasparakis M, Ikeda F (2014) Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis. Elife 3. doi: 10.7554/eLife.03422.

Kumari S, Bonnet MC, Ulvmar MH, Wolk K, Karagianni N, Witte E, Uthoff-Hachenberg C, Renauld JC, Kollias G, Toftgard R, Sabat R, Pasparakis M, Haase I (2013) Tumor necrosis factor receptor signaling in keratinocytes triggers interleukin-24-dependent psoriasis-like skin inflammation in mice. Immunity 39(5):899-911

Wohlleber D, Kashkar H, Gärtner K, Frings MK, Odenthal M, Hegenbarth S, Börner C, Arnold B, Hämmerling G, Nieswandt B, van Rooijen N, Limmer A, Cederbrant K, Heikenwalder M, Pasparakis M, Protzer U, Dienes HP, Kurts C, Krönke M, and Knolle PA (2012) TNF-induced target cell killing by CTL activated through cross-presentation. Cell Rep. 2(3):478-87

Chang J-H, Xiao Y, Hu H, Jin J, Yu J, Zhou X, Wu X, Johnson HM, Akira S, Pasparakis M, Cheng X & Sun S-C (2012) Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells. Nat Immunol 13: 481–490

Maelfait J, Roose K, Bogaert P, Sze M, Saelens X, Pasparakis M, Carpentier I, van Loo G & Beyaert R (2012) A20 (Tnfaip3) deficiency in myeloid cells protects against influenza A virus infection. PLoS Pathog 8: e1002570

Welz PS, Wullaert A, Vlantis K, Kondylis V, Fernández-Majada V, Ermolaeva M, Kirsch P, Sterner-Kock A, van Loo G, and Pasparakis M (2011) FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477(7364):330-4

Bonnet MC, Preukschat D, Welz PS, van Loo G, Ermolaeva MA, Bloch W, Haase I, and Pasparakis M (2011) The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity 35(4):572-82.

Wullaert A, Bonnet MC & Pasparakis M (2011) NF-κB in the regulation of epithelial homeostasis and inflammation. Cell Res 21: 146–158

Ikeda F, Deribe YL, Skånland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, van Wijk SJL, Goswami P, Nagy V, Terzic J, Tokunaga F, Androulidaki A, Nakagawa T, Pasparakis M, Iwai K, Sundberg JP, Schaefer L, Rittinger K, Macek B & Dikic I (2011) SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. Nature 471: 637–641

Ermolaeva MA, Michallet MC, Papadopoulou N, Utermohlen O, Kranidioti K, Kollias G, Tschopp J, Pasparakis M (2008) Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses. Nat Immunol 9(9): 1037-1046

Michallet MC, Meylan E, Ermolaeva MA, Vazquez J, Rebsamen M, Curran J, Poeck H, Bscheider M, Hartmann G, Konig M, Kalinke U, Pasparakis M, Tschopp J (2008) TRADD protein is an essential component of the RIG-like helicase antiviral pathway. Immunity 28(5): 651-661

Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G, Ermolaeva M, Veldhuizen R, Leung YH, Wang H, Liu H, Sun Y, Pasparakis M, Kopf M, Mech C, Bavari S, Peiris JS, Slutsky AS, Akira S, Hultqvist M, Holmdahl R, Nicholls J, Jiang C, Binder CJ, Penninger JM (2008) Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 133(2): 235-249

Pasparakis M, Vandenabeele P (2015) Necroptosis and its role in inflammation. Nature 517(7534):311-20

Pasparakis M, Haase I, Nestle FO. (2014) Mechanisms regulating skin immunity and inflammation. Nat Rev Immunol. 14(5):289-301

Pasparakis M (2009) Regulation of tissue homeostasis by NF-κB signalling: implications for inflammatory diseases. Nat Rev Immunol. 9 (11):778-88

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