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Project 27
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Project 27

Thomas Kufer

Characterization of the roles of NLRC5 in immune responses

Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne

Project site in progress

Our laboratory has a long-standing research interest in the molecular characterization of the function of mammalian "nucleotide-binding domain, leucine rich repeat containing proteins" (NLRs) of which many members contribute to innate and adaptive immune responses in mammals. Recently, we reported on the characterization of the human NLR protein NLRC5. NLRC5 is a cytosolic protein that can shuttle to the nucleus.

Our results show that NLRC5 specifically drives histocompatibility class I (MHC class I) but not MHC class II gene expression. Until then the existence of a dedicated regulator of MHC class I gene expression that functions in a similar manner as the NLR protein "MHC class II transcriptional activator" (CIITA) the major regulator of MHC class II expression had been hypothesized.

Our data strongly suggest that NLRC5 is such a protein. We showed that NLRC5 exerts MHC I gene regulation in a similar manner as CIITA induces MHC class II transcription by using the same DNA binding complex, termed enhanceosome. Furthermore, we reported recently, that NLRC5 affects type I interferon responses, that coordinates the immediate immune response towards viral infection. However, the underlying molecular mechanisms remained elusive.

Based on our preliminary results, we propose that the contribution of NLRC5 to either type I interferon response or the regulation of MHC class I gene expression depends on its differential sub-cellular localization. Such a dual specificity for an innate immune regulatory protein is unique and indicates the involvement of NLRC5 in multiple cellular signaling responses towards intracellular pathogens. As both presentation of antigens by MHC class I molecules and type-I interferon responses are interlinked and essentially contribute to anti-viral immunity, strongly suggest an important role of NLRC5 in orchestrating anti-viral immune responses.

This project aims at deciphering the poorly understood molecular mechanisms underlying the function of NLRC5 in anti-viral cell-autonomous immune responses.

Anticipated results of this project will provide important novel insights into fundamental processes of immunity and will help to define novel approaches for therapeutic interventions in anti-viral therapy.

List of publications resulting from the project

Ranjan P, Singh N, Kumar A, Neerincx A, Kremmer E, Cao W, Davis WG, Katz JM, Gangappa S, Lin R, Kufer TA, Sambhara S. NLRC5 interacts with RIG-I to induce a robust antiviral response against influenza virus infection. Eur J Immunol. 2014 Nov 18. doi: 10.1002/eji.201344412.

Bielig H, Lautz K, Braun PR, Menning M, Machuy N, Brügmann C, Barisic S, Eisler SA, Andree M, Zurek B, Kashkar H, Sansonetti PJ, Hausser A, Meyer TF, Kufer TA.The Cofilin Phosphatase Slingshot Homolog 1 (SSH1) Links NOD1 Signaling to Actin Remodeling. PLoS Pathog. 2014 Sep 4;10(9):e1004351. doi 10.1371/journal.ppat.1004351. eCollection 2014 Sep.

Neerincx A, Jakobshagen K, Utermöhlen O, Büning H, Steimle V, Kufer TA. The N-Termin al Domain of NLRC5 Confers Transcriptional Activity for MHC Class I and II Gene Expression. J Immunol. 2014 Sep 15;193(6):3090-100. doi: 10.4049/jimmunol.1401065.

Andree M, Seeger JM, Schüll S, Coutelle O, Wagner-Stippich D, Wiegmann K, Wunderlich CM, Brinkmann K, Broxtermann P, Witt A, Fritsch M, Martinelli P, Bielig H, Lamkemeyer T, Rugarli EI, Kaufmann T, Sterner-Kock A, Wunderlich FT, Villunger A, Martins LM, Krönke M, Kufer TA, Utermöhlen O, Kashkar H. BID-dependent release of mitochondrial SMAC dampens XIAP-mediated immunity against Shigella. EMBO J. 2014 Jul 23. pii: e201387244. [Epub ahead of print]

Thay B, Damm A, Kufer TA, Wai SN, Oscarsson J. Aggregatibacter actinomycetemcomitans Outer Membrane Vesicles Are Internalized in Human Host Cells and Trigger NOD1- and NOD2-Dependent NF-κB Activation. Infect Immun. 2014 Oct;82(10):4034-46. doi: 10.1128/IAI.01980-14.

Mayle S, Boyle JP, Sekine E, Zurek B, Kufer TA, Monie TP. Engagement of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) by receptor-interacting protein 2 (RIP2) is insufficient for signal transduction. J Biol Chem. 2014 Aug 15;289(33):22900-14. doi: 10.1074/jbc.M114.557900.
Irving AT, Mimuro H, Kufer TA, Lo C, Wheeler R, Turner LJ, Thomas BJ, Malosse C, Gantier MP, Casillas LN, Votta BJ, Bertin J, Boneca IG, Sasakawa C, Philpott DJ, Ferrero RL, Kaparakis-Liaskos M. The immune receptor NOD1 and kinase RIP2 interact with bacterial peptidoglycan on early endosomes to promote autophagy and inflammatory signaling. Cell Host Microbe. 2014 May 14;15(5):623-35. doi: 10.1016/j.chom.2014.04.001.

Neerincx A, Castro W, Guarda G, Kufer TA. NLRC5, at the Heart of Antigen Presentation.
Front Immunol. 2013 Nov 22;4:397. doi: 10.3389/fimmu.2013.00397. Review.

Menning M, Kufer TA. A role for the Ankyrin repeat containing protein Ankrd17 in Nod1- and Nod2-mediated inflammatory responses. FEBS Lett. 2013 Jul 11;587(14):2137-42. doi: 10.1016/j.febslet.2013.05.037.

Damm A, Lautz K, Kufer TA. R oles of NLRP10 in innate and adaptive immunity.
Microbes Infect. 2013 Jun;15(6-7):516-23. doi: 10.1016/j.micinf.2013.03.008. Review.

Zurek B, Schoultz I, Neerincx A, Napolitano LM, Birkner K, Bennek E, Sellge G, Lerm M, Meroni G, Söderholm JD, Kufer TA. TRIM27 negatively regulates NOD2 by ubiquitination and proteasomal degradation. PLoS One. 2012;7(7):e41255. doi: 10.1371/journal.pone.0041255.

Lecat A, Di Valentin E, Somja J, Jourdan S, Fillet M, Kufer TA, Habraken Y, Sadzot C, Louis E, Delvenne P, Piette J, Legrand-Poels S. The c-Jun N-terminal kinase (JNK)-binding protein (JNKBP1) acts as a negative regulator of NOD2 protein signaling by inhibiting its oligomerization process. J Biol Chem. 2012 Aug 24;287(35):29213-26. doi: 10.1074/jbc.M112.355545.

Lautz K, Damm A, Menning M, Wenger J, Adam AC, Zigrino P, Kremmer E, Kufer TA. NLRP10 enhances Shigella-induced pro-inflammatory responses. Cell Microbiol. 2012 Oct;14(10):1568-83. doi: 10.1111/j.1462-5822.2012.01822.x.

Neerincx A, Rodriguez GM, Steimle V, Kufer TA. NLRC5 controls basal MHC class I gene expression in an MHC enhanceosome-dependent manner. J Immunol. 2012 May 15;188(10):4940-50. doi: 10.4049/jimmunol.1103136.

Zurek B, Proell M, Wagner RN, Schwarzenbacher R, Kufer TA. Mutational analysis of human NOD1 and NOD2 NACHT domains reveals different modes of activation. Innate Immun. 2012 Feb;18(1):100-11. doi: 10.1177/1753425910394002.

Gut Microbes. 2011 Sep 1;2(5):274-9. doi: 10.4161/gmic.2.5.18091. Review.

Maekawa T, Kufer TA, Schulze-Lefert P. NLR functions in plant and animal immune systems: so far and yet so close. Nat Immunol. 2011 Aug 18;12(9):817-26. doi: 10.1038/ni.2083. Review.

Zurek B, Bielig H, Kufer TA. Cell-based reporter assay to analyze activation of Nod1 and Nod2. Methods Mol Biol. 2011;748:107-19. doi: 10.1007/978-1-61779-139-0_7.

Staquet MJ, Carrouel F, Keller JF, Baudouin C, Msika P, Bleicher F, Kufer TA, Farges JC. Pattern-recognition receptors in pulp defense. Adv Dent Res. 2011 Jul;23(3):296-301. doi: 10.1177/0022034511405390. Review.

Bielig H, Rompikuntal PK, Dongre M, Zurek B, Lindmark B, Ramstedt M, Wai SN, Kufer TA. NOD-like receptor activation by outer membrane vesicles from Vibrio cholerae non-O1 non-O139 strains is modulated by the quorum-sensing regulator HapR. Infect Immun. 2011 Apr;79(4):1418-27. doi: 10.1128/IAI.00754-10

Kufer TA, Sansonetti PJ. NLR functions beyond pathogen recognition. Nat Immunol. 2011 Feb;12(2):121-8. doi: 10.1038/ni.1985.

Keller JF, Carrouel F, Staquet MJ, Kufer TA, Baudouin C, Msika P, Bleicher F, Farges JC. Expression of NOD2 is increased in inflamed human dental pulps and lipoteichoic acid-stimulated odontoblast-like cells. Innate Immun. 2011 Feb;17(1):29-34. doi: 10.1177/1753425909348527.