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The paracaspase MALT1 in psoriasis

  • Stephan Hailfinger

    Stephan Hailfinger joined the PhD program “Cancer and Immunology” and received his PhD from the University of Lausanne, Switzerland. After his postdoctoral research in the laboratory of Margot Thome in Lausanne, he became an Emmy Noether group leader at the Interfaculty Institute of Biochemistry (IFIB) of the University of Tübingen. Recently, he joined the Department of Medicine A of the University Hospital Münster as full professor. Stephan Hailfinger is interested to shed light on the signaling events leading to lymphocyte activation and lymphoma development.

     ORCID logo EMAIL logo     and Klaus Schulze-Osthoff

    Klaus Schulze-Osthoff obtained his PhD at the University of Münster and performed postdoctoral research with Walter Fiers, Peter Krammer and Patrick Baeuerle at the Gent Laboratory of Molecular Biology, the German Cancer Research Center Heidelberg and the University of Freiburg. Following professorships in Molecular Gastroenterology, Immunology and Cell Biology in Tübingen and Münster, he became founding director of the Institute of Molecular Medicine in Düsseldorf. Currently, he is head of the Department of Molecular Medicine at the Interfaculty Institute of Biochemistry (IFIB) of the University of Tübingen, and affiliated to the German Cancer Research Center. His work concentrates on tumor immunology with a particular focus on the role of transcription factor NF-κB in tumor inflammation, immune escape and therapy resistance. He has been a member of the IZKF Münster from 1999 to 2002.
Published/Copyright: July 1, 2021
Biological Chemistry
From the journal Biological Chemistry Volume 402 Issue 12

Abstract

Psoriasis is a frequent autoimmune-related skin disease, which involves various cell types such as T cells, keratinocytes and dendritic cells. Genetic variations, such as mutations of CARD14, can promote the development of the disease. CARD14 mutations as well as the stimulation of immune and cytokine receptors activate the paracaspase MALT1, a potent activator of the transcription factors NF-κB and AP-1. The disease-promoting role of MALT1 for psoriasis is mediated by both its protease activity as well as its molecular scaffold function. Here, we review the importance of MALT1-mediated signaling and its therapeutic implications in psoriasis.

Keywords: BCL10; CARD14; CBM complex; NF-κB; paracaspase; protease
Corresponding author: Stephan Hailfinger, Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Domagkstr. 3, D-48149 Münster, Germany, E-mail:

This article is a contribution to the issue highlighting the 25th Anniversary of the Interdisciplinary Centre for Clinical Research (IZKF) Münster.

Funding source: Collaborative Research Center Transregio

Award Identifier / Grant number: SFB/TR 209

Award Identifier / Grant number: SFB/TR 156

Funding source: Deutsche Forschungsgemeinschaft 10.13039/501100001659

Funding source: Deutsche Krebshilfe 10.13039/501100005972

About the authors

Stephan Hailfinger

Stephan Hailfinger joined the PhD program “Cancer and Immunology” and received his PhD from the University of Lausanne, Switzerland. After his postdoctoral research in the laboratory of Margot Thome in Lausanne, he became an Emmy Noether group leader at the Interfaculty Institute of Biochemistry (IFIB) of the University of Tübingen. Recently, he joined the Department of Medicine A of the University Hospital Münster as full professor. Stephan Hailfinger is interested to shed light on the signaling events leading to lymphocyte activation and lymphoma development.

Klaus Schulze-Osthoff

Klaus Schulze-Osthoff obtained his PhD at the University of Münster and performed postdoctoral research with Walter Fiers, Peter Krammer and Patrick Baeuerle at the Gent Laboratory of Molecular Biology, the German Cancer Research Center Heidelberg and the University of Freiburg. Following professorships in Molecular Gastroenterology, Immunology and Cell Biology in Tübingen and Münster, he became founding director of the Institute of Molecular Medicine in Düsseldorf. Currently, he is head of the Department of Molecular Medicine at the Interfaculty Institute of Biochemistry (IFIB) of the University of Tübingen, and affiliated to the German Cancer Research Center. His work concentrates on tumor immunology with a particular focus on the role of transcription factor NF-κB in tumor inflammation, immune escape and therapy resistance. He has been a member of the IZKF Münster from 1999 to 2002.

Acknowledgments

We thank Anja Schmitt for helpful discussion and corrections.

  1. Author contributions: Both authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This work was supported by the Collaborative Research Center Transregio SFB/TR 156 (to S.H.), SFB/TR 209 (to K.S.-O. and S.H.), the Emmy-Noether program of the Deutsche Forschungsgemeinschaft and the Deutsche Krebshilfe (S.H.).

  3. Conflict of interest statement: The authors declare no conflict of interest.

References

Afonina, I.S., Van Nuffel, E., Baudelet, G., Driege, Y., Kreike, M., Staal, J., and Beyaert, R. (2016). The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes. EMBO Rep. 17: 914–927, https://doi.org/10.15252/embr.201642109.Search in Google Scholar PubMed PubMed Central

Baens, M., Bonsignore, L., Somers, R., Vanderheydt, C., Weeks, S.D., Gunnarsson, J., Nilsson, E., Roth, R.G., Thome, M., and Marynen, P. (2014). MALT1 auto-proteolysis is essential for NF-kappaB-dependent gene transcription in activated lymphocytes. PloS One 9: e103774, https://doi.org/10.1371/journal.pone.0103774.Search in Google Scholar PubMed PubMed Central

Demeyer, A., Driege, Y., Skordos, I., Coudenys, J., Lemeire, K., Elewaut, D., Staal, J., and Beyaert, R. (2020). Long-term MALT1 inhibition in adult mice without severe systemic autoimmunity. iScience 23: 101557, https://doi.org/10.1016/j.isci.2020.101557.Search in Google Scholar PubMed PubMed Central

Deng, Y., Chang, C., and Lu, Q. (2016). The inflammatory response in psoriasis: a comprehensive review. Clin. Rev. Allergy Immunol. 50: 377–389, https://doi.org/10.1007/s12016-016-8535-x.Search in Google Scholar PubMed

Elton, L., Carpentier, I., Staal, J., Driege, Y., Haegman, M., and Beyaert, R. (2016). MALT1 cleaves the E3 ubiquitin ligase HOIL-1 in activated T cells, generating a dominant negative inhibitor of LUBAC-induced NF-κB signaling. FEBS J. 283: 403–412, https://doi.org/10.1111/febs.13597.Search in Google Scholar PubMed

Gewies, A., Gorka, O., Bergmann, H., Pechloff, K., Petermann, F., Jeltsch, K.M., Rudelius, M., Kriegsmann, M., Weichert, W., Horsch, M., et al.. (2014). Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation. Cell Rep. 9: 1292–1305, https://doi.org/10.1016/j.celrep.2014.10.044.Search in Google Scholar PubMed

Grondona, P., Bucher, P., Schulze-Osthoff, K., Hailfinger, S., and Schmitt, A. (2018). NF-κB activation in lymphoid malignancies: genetics, signaling, and targeted therapy. Biomedicines 6: 38, https://doi.org/10.3390/biomedicines6020038.Search in Google Scholar PubMed PubMed Central

Hailfinger, S., Lenz, G., and Thome, M. (2014). Targeting B-cell lymphomas with inhibitors of the MALT1 paracaspase. Curr. Opin. Chem. Biol. 23: 47–55, https://doi.org/10.1016/j.cbpa.2014.09.025.Search in Google Scholar PubMed

Hailfinger, S., Schmitt, A., and Schulze-Osthoff, K. (2016). The paracaspase MALT1 dampens NF-κB signalling by cleaving the LUBAC subunit HOIL-1. FEBS J. 283: 400–402, https://doi.org/10.1111/febs.13639.Search in Google Scholar PubMed

Holliday, M.J., Witt, A., Rodriguez Gama, A., Walters, B.T., Arthur, C.P., Halfmann, R., Rohou, A., Dueber, E.C., and Fairbrother, W.J. (2019). Structures of autoinhibited and polymerized forms of CARD9 reveal mechanisms of CARD9 and CARD11 activation. Nat. Commun. 10: 3070, https://doi.org/10.1038/s41467-019-10953-z.Search in Google Scholar PubMed PubMed Central

Howes, A., O’Sullivan, P.A., Breyer, F., Ghose, A., Cao, L., Krappmann, D., Bowcock, A.M., and Ley, S.C. (2016). Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation. Biochem. J. 473: 1759–1768, https://doi.org/10.1042/bcj20160270.Search in Google Scholar PubMed PubMed Central

Israel, L., Bardet, M., Huppertz, A., Mercado, N., Ginster, S., Unterreiner, A., Schlierf, A., Goetschy, J.F., Zerwes, H.G., Roth, L., et al.. (2018). A CARD10-dependent tonic signalosome activates MALT1 paracaspase and regulates IL-17/TNF-α-driven keratinocyte inflammation. J. Invest. Dermatol. 138: 2075–2079, https://doi.org/10.1016/j.jid.2018.03.1503.Search in Google Scholar PubMed

Jaworski, M., Marsland, B.J., Gehrig, J., Held, W., Favre, S., Luther, S.A., Perroud, M., Golshayan, D., Gaide, O., and Thome, M. (2014). Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity. EMBO J. 33: 2765–2781, https://doi.org/10.15252/embj.201488987.Search in Google Scholar PubMed PubMed Central

Jeltsch, K.M., Hu, D., Brenner, S., Zoller, J., Heinz, G.A., Nagel, D., Vogel, K.U., Rehage, N., Warth, S.C., Edelmann, S.L., et al.. (2014). Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation. Nat. Immunol. 15: 1079–1089, https://doi.org/10.1038/ni.3008.Search in Google Scholar PubMed

Juilland, M. and Thome, M. (2018). Holding all the CARDs: how MALT1 controls CARMA/CARD-dependent signaling. Front. Immunol. 9: 1927, https://doi.org/10.3389/fimmu.2018.01927.Search in Google Scholar PubMed PubMed Central

Klein, T., Fung, S.Y., Renner, F., Blank, M.A., Dufour, A., Kang, S., Bolger-Munro, M., Scurll, J.M., Priatel, J.J., Schweigler, P., et al.. (2015). The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling. Nat. Commun. 6: 8777, https://doi.org/10.1038/ncomms9777.Search in Google Scholar PubMed PubMed Central

Lande, R., Botti, E., Jandus, C., Dojcinovic, D., Fanelli, G., Conrad, C., Chamilos, G., Feldmeyer, L., Marinari, B., Chon, S., et al.. (2014). The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis. Nat. Commun. 5: 5621, https://doi.org/10.1038/ncomms6621.Search in Google Scholar PubMed

Lowes, M.A., Suarez-Farinas, M., and Krueger, J.G. (2014). Immunology of psoriasis. Annu. Rev. Immunol. 32: 227–255, https://doi.org/10.1146/annurev-immunol-032713-120225.Search in Google Scholar PubMed PubMed Central

Manils, J., Webb, L.V., Howes, A., Janzen, J., Boeing, S., Bowcock, A.M., and Ley, S.C. (2020). CARD14(E138A) signalling in keratinocytes induces TNF-dependent skin and systemic inflammation. eLife 9: e56720, https://doi.org/10.7554/eLife.56720.Search in Google Scholar PubMed PubMed Central

Martin, K., Junker, U., Tritto, E., Sutter, E., Rubic-Schneider, T., Morgan, H., Niwa, S., Li, J., Schlapbach, A., Walker, D., et al.. (2020). Pharmacological inhibition of MALT1 protease leads to a progressive IPEX-Like pathology. Front. Immunol. 11: 745, https://doi.org/10.3389/fimmu.2020.00745.Search in Google Scholar PubMed PubMed Central

Mellett, M., Meier, B., Mohanan, D., Schairer, R., Cheng, P., Satoh, T.K., Kiefer, B., Ospelt, C., Nobbe, S., Thome, M., et al.. (2018). CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo. J. Invest. Dermatol. 138: 2010–2023, https://doi.org/10.1016/j.jid.2018.03.1525.Search in Google Scholar PubMed

Nair, R.P., Duffin, K.C., Helms, C., Ding, J., Stuart, P.E., Goldgar, D., Gudjonsson, J.E., Li, Y., Tejasvi, T., Feng, B.J., et al.. (2009). Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nat. Genet. 41: 199–204, https://doi.org/10.1038/ng.311.Search in Google Scholar PubMed PubMed Central

Ruland, J., and Hartjes, L. (2019). CARD-BCL-10-MALT1 signalling in protective and pathological immunity. Nat. Rev. Immunol. 19: 118–134, https://doi.org/10.1038/s41577-018-0087-2.Search in Google Scholar PubMed

Staal, J., Driege, Y., Haegman, M., Kreike, M., Iliaki, S., Vanneste, D., Lork, M., Afonina, I.S., Braun, H., and Beyaert, R. (2021). Defining the combinatorial space of PKC::CARD-CC signal transduction nodes. FEBS J. 288: 1630–1647, https://doi.org/10.1111/febs.15522.Search in Google Scholar PubMed

Tanaka, M., Kobiyama, K., Honda, T., Uchio-Yamada, K., Natsume-Kitatani, Y., Mizuguchi, K., Kabashima, K., and Ishii, K.J. (2018). Essential role of CARD14 in murine experimental psoriasis. J. Immunol. 200: 71–81, https://doi.org/10.4049/jimmunol.1700995.Search in Google Scholar PubMed

Ten Bergen, L.L., Petrovic, A., Aarebrot, A.K., and Appel, S. (2020). Current knowledge on autoantigens and autoantibodies in psoriasis. Scand. J. Immunol. 92: e12945, https://doi.org/10.1111/sji.12945.Search in Google Scholar PubMed

Van Nuffel, E., Schmitt, A., Afonina, I.S., Schulze-Osthoff, K., Beyaert, R., and Hailfinger, S. (2017). CARD14-mediated activation of paracaspase MALT1 in keratinocytes: implications for psoriasis. J. Invest. Dermatol. 137: 569–575, https://doi.org/10.1016/j.jid.2016.09.031.Search in Google Scholar PubMed

Van Nuffel, E., Staal, J., Baudelet, G., Haegman, M., Driege, Y., Hochepied, T., Afonina, I.S., and Beyaert, R. (2020). MALT1 targeting suppresses CARD14-induced psoriatic dermatitis in mice. EMBO Rep. 21: e49237, https://doi.org/10.15252/embr.201949237.Search in Google Scholar PubMed PubMed Central

Wang, M., Zhang, S., Zheng, G., Huang, J., Songyang, Z., Zhao, X., and Lin, X. (2018). Gain-of-function mutation of Card14 leads to spontaneous psoriasis-like skin inflammation through enhanced keratinocyte response to IL-17A. Immunity 49: 66–79 e5, https://doi.org/10.1016/j.immuni.2018.05.012.Search in Google Scholar PubMed

Xia, X., Cao, G., Sun, G., Zhu, L., Tian, Y., Song, Y., Guo, C., Wang, X., Zhong, J., Zhou, W., et al.. (2020). GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis. J. Clin. Invest. 130: 5180–5196, https://doi.org/10.1172/jci129269.Search in Google Scholar PubMed PubMed Central

Zhang, S., Wang, M., Wang, C., Wang, G., Sun, K., Xiong, S., Cheng, L., Yang, D., Lin, X., and Zhao, X. (2021). Intrinsic abnormalities of keratinocytes initiate skin inflammation through the IL-23/T17 axis in a MALT1-dependent manner. J. Immunol. 206: 839–848, https://doi.org/10.4049/jimmunol.2001031.Search in Google Scholar PubMed

Received: 2021-05-03
Accepted: 2021-06-02
Published Online: 2021-07-01
Published in Print: 2021-11-25

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Highlight: Molecular Determinants of Health and Disease - 25th Anniversary of the InterdisciplinaryCenter Clinical Research Münster
  3. Molecular determinants of health and disease
  4. Role of the gut microbiota in airway immunity and host defense against respiratory infections
  5. Dynamic phospho-modification of viral proteins as a crucial regulatory layer of influenza A virus replication and innate immune responses
  6. Molecular mechanisms of vasculopathy and coagulopathy in COVID-19
  7. Astrocytic potassium and calcium channels as integrators of the inflammatory and ischemic CNS microenvironment
  8. Epitranscriptomic modifications in acute myeloid leukemia: m6A and 2′-O-methylation as targets for novel therapeutic strategies
  9. Molecular determinants of therapy response of venetoclax-based combinations in acute myeloid leukemia
  10. Pseudomonas aeruginosa and Staphylococcus aureus virulence factors as biomarkers of infection
  11. Controllers of cutaneous regulatory T cells: ultraviolet radiation and the skin microbiome
  12. The paracaspase MALT1 in psoriasis
  13. The cAMP responsive element modulator (CREM) is a regulator of CD4+ T cell function
  14. Quantifying salt sensitivity
  15. Life sciences and mass spectrometry: some personal reflections
https://doi.org/10.1515/hsz-2021-0250
Keywords for this article
BCL10; CARD14; CBM complex; NF-κB; paracaspase; protease

Articles in the same Issue

  1. Frontmatter
  2. Highlight: Molecular Determinants of Health and Disease - 25th Anniversary of the InterdisciplinaryCenter Clinical Research Münster
  3. Molecular determinants of health and disease
  4. Role of the gut microbiota in airway immunity and host defense against respiratory infections
  5. Dynamic phospho-modification of viral proteins as a crucial regulatory layer of influenza A virus replication and innate immune responses
  6. Molecular mechanisms of vasculopathy and coagulopathy in COVID-19
  7. Astrocytic potassium and calcium channels as integrators of the inflammatory and ischemic CNS microenvironment
  8. Epitranscriptomic modifications in acute myeloid leukemia: m6A and 2′-O-methylation as targets for novel therapeutic strategies
  9. Molecular determinants of therapy response of venetoclax-based combinations in acute myeloid leukemia
  10. Pseudomonas aeruginosa and Staphylococcus aureus virulence factors as biomarkers of infection
  11. Controllers of cutaneous regulatory T cells: ultraviolet radiation and the skin microbiome
  12. The paracaspase MALT1 in psoriasis
  13. The cAMP responsive element modulator (CREM) is a regulator of CD4+ T cell function
  14. Quantifying salt sensitivity
  15. Life sciences and mass spectrometry: some personal reflections
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