The molecular role of CARMA2 in psoriasis
Final Report Abstract
Psoriasis is a very common autoimmune disease which is characterized by chronic activation of the immune system and epidermal hyperplasia. In this project we shed light on how keratinocytes become activated and which molecular mechanisms lead to the induction of antimicrobial peptides as well as proinflammatory chemokines and cytokines. We and others could demonstrate that CARMA2 mutations, which are found in psoriasis patients, drive the constitutive formation of a CARMA2-BCL10-MALT1 (CBM) complex in keratinocytes. CBM complex assembly promotes the activation of the transcription factor NF-κB, a well-known regulator of proinflammatory mediators. MALT1 acts not only as a scaffold protein but also as a protease and both its functions are essential for an optimal NF-κB activation. MALT1 protease inhibitors reduce the expression of cytokines and chemokines that are associated with psoriasis development, such as IL-17C, TNFα and CXCL-8, both in vitro and in vivo, highlighting their therapeutic potential. Infections, proinflammatory cytokines and mutations detected in psoriasis patients induce the expression of the IκBζ protein in immune cells and keratinocytes. IκBζ functions as a crucial transcriptional regulator for a specific subset of NF-κB target genes, the majority of which play an important role in the pathogenesis of psoriasis. Interestingly, global IκBζ knock-out in mice confers resistance to experimentally induced psoriasis, making IκBζ a bona fide drug target. Together with our collaboration partners, we discovered that IκBζ expression in keratinocytes, unlike in most immune cells, is crucial for the induction of skin inflammation. Furthermore, we could identify previously unknown IκBζ inducers in the skin, such as agonists of the receptor Dectin-1 or IL-36. As IκBζ lacks a targetable enzymatic activity, we investigated how IκBζ is regulated by posttranslational modifications. Using mass spectrometric analyses, we have identified several phosphorylation sites, which are mainly located in the N-terminus of IκBζ. We focused on a highly conserved triple threonine cluster that is presumably modified by the RAS-MAPK pathway, thereby negatively regulating the transcriptional activity of IκBζ. Collectively, we contributed with our research to an improved understanding of the keratinocyte-mediated immune response. We identified MALT1 and IκBζ as important regulators of proinflammatory signaling in keratinocytes and thus as promising targets for therapeutic intervention in inflammatory skin diseases.
Publications
- (2015). IkappaBzeta is a key driver in the development of psoriasis. Proc Natl Acad Sci U S A 112, E5825-5833
Johansen, C., Mose, M., Ommen, P., Bertelsen, T., Vinter, H., Hailfinger, S., Lorscheid, S., Schulze-Osthoff, K., and Iversen, L.
(See online at https://doi.org/10.1073/pnas.1509971112) - (2016). MALT1 Protease Activity Controls the Expression of Inflammatory Genes in Keratinocytes upon Zymosan Stimulation. J Invest Dermatol 136, 788-797
Schmitt, A., Grondona, P., Maier, T., Brandle, M., Schonfeld, C., Jager, G., Kosnopfel, C., Eberle, F.C., Schittek, B., Schulze-Osthoff, K., Yazdi, A.S., and Hailfinger, S.
(See online at https://doi.org/10.1016/j.jid.2015.12.027) - (2017). CARD14-Mediated Activation of Paracaspase MALT1 in Keratinocytes: Implications for Psoriasis. J Invest Dermatol 137, 569-575
Van Nuffel, E., Schmitt, A., Afonina, I.S., Schulze-Osthoff, K., Beyaert, R., and Hailfinger, S.
(See online at https://doi.org/10.1016/j.jid.2016.09.031) - (2018). Correspondence: T cells are compromised in tetracycline transactivator transgenic mice. Cell Death Differ 25, 634-636
Schmitt, A., Schulze-Osthoff, K., and Hailfinger, S.
(See online at https://doi.org/10.1038/s41418-017-0042-y) - (2018). IkappaBzeta is a key transcriptional regulator of IL-36-driven psoriasisrelated gene expression in keratinocytes. Proc Natl Acad Sci U S A 115, 10088-10093
Muller, A., Hennig, A., Lorscheid, S., Grondona, P., Schulze-Osthoff, K., Hailfinger, S., and Kramer, D.
(See online at https://doi.org/10.1073/pnas.1801377115) - (2019). Keratinocyte-derived IkappaBzeta drives psoriasis and associated systemic inflammation. JCI Insight 4
Lorscheid, S., Muller, A., Loffler, J., Resch, C., Bucher, P., Kurschus, F.C., Waisman, A., Schakel, K., Hailfinger, S., Schulze-Osthoff, K., and Kramer, D.
(See online at https://doi.org/10.1172/jci.insight.130835) - (2020). Targeting chronic NFAT activation with calcineurin inhibitors in diffuse large B-cell lymphoma. Blood 135, 121-132
Bucher, P., Erdmann, T., Grondona, P., Xu, W., Schmitt, A., Schurch, C., Zapukhlyak, M., Schonfeld, C., Serfling, E., Kramer, D., Grau, M., Klener, P., Lengerke, C., Schulze-Osthoff, K., Lenz, G., and Hailfinger, S.
(See online at https://doi.org/10.1182/blood.2019001866) - (2020). The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis. J Clin Invest 130, 5765-5781
Muller, A., Dickmanns, A., Resch, C., Schakel, K., Hailfinger, S., Dobbelstein, M., Schulze- Osthoff, K., and Kramer, D.
(See online at https://doi.org/10.1172/JCI134217) - (2020). Threonine Phosphorylation of IkappaBzeta Mediates Inhibition of Selective Proinflammatory Target Genes. J Invest Dermatol
Grondona, P., Bucher, P., Schmitt, A., Schonfeld, C., Streibl, B., Muller, A., Essmann, F., Liberatori, S., Mohammed, S., Hennig, A., Kramer, D., Schulze-Osthoff, K., and Hailfinger, S.
(See online at https://doi.org/10.1016/j.jid.2019.12.036) - (2021). Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL. Blood
Schmitt, A., Xu, W., Bucher, P., Grimm, M., Konantz, M., Horn, H., Zapukhlyak, M., Berning, P., Brändle, M., Jarboui, M., Schönfeld, C., Boldt, K., Rosenwald, A., Ott, G., Grau, M., Klener, P., Vockova, P., Lengerke, C., Lenz, G., Schulze-Osthoff, K., and Hailfinger, S.
(See online at https://doi.org/10.1182/blood.2020009404)
