Targeting TRAF6 E3 ligase activity with a small-molecule inhibitor combats autoimmunity

Research output: Contribution to journalArticleResearchpeer review

Authors

  • Jara K Brenke
  • Grzegorz M Popowicz
  • Kenji Schorpp
  • Ina Rothenaigner
  • Manfred Roesner
  • Isabel Meininger
  • Cédric Kalinski
  • Larissa Ringelstetter
  • Omar R'kyek
  • Gerrit Jürjens
  • Michelle Vincendeau
  • Oliver Plettenburg
  • Michael Sattler
  • Daniel Krappmann
  • Kamyar Hadian

Research Organisations

External Research Organisations

  • Helmholtz Zentrum München - German Research Center for Environmental Health
  • Technical University of Munich (TUM)
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Details

Original languageEnglish
Pages (from-to)13191-13203
Number of pages13
JournalJournal of Biological Chemistry
Volume293
Issue number34
Early online date27 Jun 2018
Publication statusPublished - Aug 2018

Abstract

Constitutive NF-κB signaling represents a hallmark of chronic inflammation and autoimmune diseases. The E3 ligase TNF receptor-associated factor 6 (TRAF6) acts as a key regulator bridging innate immunity, pro-inflammatory cytokines, and antigen receptors to the canonical NF-κB pathway. Structural analysis and point mutations have unraveled the essential role of TRAF6 binding to the E2-conjugating enzyme ubiquitin-conjugating enzyme E2 N (Ubc13 or UBE2N) to generate Lys63-linked ubiquitin chains for inflammatory and immune signal propagation. Genetic mutations disrupting TRAF6-Ubc13 binding have been shown to reduce TRAF6 activity and, consequently, NF-κB activation. However, to date, no small-molecule modulator is available to inhibit the TRAF6-Ubc13 interaction and thereby counteract NF-κB signaling and associated diseases. Here, using a high-throughput small-molecule screening approach, we discovered an inhibitor of the TRAF6-Ubc13 interaction that reduces TRAF6-Ubc13 activity both in vitro and in cells. We found that this compound, C25-140, impedes NF-κB activation in various immune and inflammatory signaling pathways also in primary human and murine cells. Importantly, C25-140 ameliorated inflammation and improved disease outcomes of autoimmune psoriasis and rheumatoid arthritis in preclinical in vivo mouse models. Hence, the first-in-class TRAF6-Ubc13 inhibitor C25-140 expands the toolbox for studying the impact of the ubiquitin system on immune signaling and underscores the importance of TRAF6 E3 ligase activity in psoriasis and rheumatoid arthritis. We propose that inhibition of TRAF6 activity by small molecules represents a promising novel strategy for targeting autoimmune and chronic inflammatory diseases.

Keywords

    Animals, Arthritis, Rheumatoid/drug therapy, Autoimmune Diseases/drug therapy, HEK293 Cells, High-Throughput Screening Assays, Humans, Inflammation/drug therapy, Intracellular Signaling Peptides and Proteins, Male, Mice, Mice, Inbred BALB C, Protein Interaction Maps, Psoriasis/drug therapy, Small Molecule Libraries/pharmacology, TNF Receptor-Associated Factor 6/antagonists & inhibitors, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/antagonists & inhibitors, Ubiquitin-Conjugating Enzymes/antagonists & inhibitors

ASJC Scopus subject areas

Sustainable Development Goals

Cite this

Targeting TRAF6 E3 ligase activity with a small-molecule inhibitor combats autoimmunity. / Brenke, Jara K; Popowicz, Grzegorz M; Schorpp, Kenji et al.
In: Journal of Biological Chemistry, Vol. 293, No. 34, 08.2018, p. 13191-13203.

Research output: Contribution to journalArticleResearchpeer review

Brenke, JK, Popowicz, GM, Schorpp, K, Rothenaigner, I, Roesner, M, Meininger, I, Kalinski, C, Ringelstetter, L, R'kyek, O, Jürjens, G, Vincendeau, M, Plettenburg, O, Sattler, M, Krappmann, D & Hadian, K 2018, 'Targeting TRAF6 E3 ligase activity with a small-molecule inhibitor combats autoimmunity', Journal of Biological Chemistry, vol. 293, no. 34, pp. 13191-13203. https://doi.org/10.1074/jbc.RA118.002649
Brenke, J. K., Popowicz, G. M., Schorpp, K., Rothenaigner, I., Roesner, M., Meininger, I., Kalinski, C., Ringelstetter, L., R'kyek, O., Jürjens, G., Vincendeau, M., Plettenburg, O., Sattler, M., Krappmann, D., & Hadian, K. (2018). Targeting TRAF6 E3 ligase activity with a small-molecule inhibitor combats autoimmunity. Journal of Biological Chemistry, 293(34), 13191-13203. https://doi.org/10.1074/jbc.RA118.002649
Brenke JK, Popowicz GM, Schorpp K, Rothenaigner I, Roesner M, Meininger I et al. Targeting TRAF6 E3 ligase activity with a small-molecule inhibitor combats autoimmunity. Journal of Biological Chemistry. 2018 Aug;293(34):13191-13203. Epub 2018 Jun 27. doi: 10.1074/jbc.RA118.002649
Brenke, Jara K ; Popowicz, Grzegorz M ; Schorpp, Kenji et al. / Targeting TRAF6 E3 ligase activity with a small-molecule inhibitor combats autoimmunity. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 34. pp. 13191-13203.
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abstract = "Constitutive NF-κB signaling represents a hallmark of chronic inflammation and autoimmune diseases. The E3 ligase TNF receptor-associated factor 6 (TRAF6) acts as a key regulator bridging innate immunity, pro-inflammatory cytokines, and antigen receptors to the canonical NF-κB pathway. Structural analysis and point mutations have unraveled the essential role of TRAF6 binding to the E2-conjugating enzyme ubiquitin-conjugating enzyme E2 N (Ubc13 or UBE2N) to generate Lys63-linked ubiquitin chains for inflammatory and immune signal propagation. Genetic mutations disrupting TRAF6-Ubc13 binding have been shown to reduce TRAF6 activity and, consequently, NF-κB activation. However, to date, no small-molecule modulator is available to inhibit the TRAF6-Ubc13 interaction and thereby counteract NF-κB signaling and associated diseases. Here, using a high-throughput small-molecule screening approach, we discovered an inhibitor of the TRAF6-Ubc13 interaction that reduces TRAF6-Ubc13 activity both in vitro and in cells. We found that this compound, C25-140, impedes NF-κB activation in various immune and inflammatory signaling pathways also in primary human and murine cells. Importantly, C25-140 ameliorated inflammation and improved disease outcomes of autoimmune psoriasis and rheumatoid arthritis in preclinical in vivo mouse models. Hence, the first-in-class TRAF6-Ubc13 inhibitor C25-140 expands the toolbox for studying the impact of the ubiquitin system on immune signaling and underscores the importance of TRAF6 E3 ligase activity in psoriasis and rheumatoid arthritis. We propose that inhibition of TRAF6 activity by small molecules represents a promising novel strategy for targeting autoimmune and chronic inflammatory diseases.",
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TY - JOUR

T1 - Targeting TRAF6 E3 ligase activity with a small-molecule inhibitor combats autoimmunity

AU - Brenke, Jara K

AU - Popowicz, Grzegorz M

AU - Schorpp, Kenji

AU - Rothenaigner, Ina

AU - Roesner, Manfred

AU - Meininger, Isabel

AU - Kalinski, Cédric

AU - Ringelstetter, Larissa

AU - R'kyek, Omar

AU - Jürjens, Gerrit

AU - Vincendeau, Michelle

AU - Plettenburg, Oliver

AU - Sattler, Michael

AU - Krappmann, Daniel

AU - Hadian, Kamyar

N1 - Funding information: This work was supported by grants from the Life Science Foundation (to K. H.) and the SFB 1054 project A04 (to D. K.). A patent for the clinical use of C25-140 has been published by the European patent office. This article contains Figs. S1–S8. 1 Present address: AbbVie Deutschland GmbH, 65189 Wiesbaden, Germany.

PY - 2018/8

Y1 - 2018/8

N2 - Constitutive NF-κB signaling represents a hallmark of chronic inflammation and autoimmune diseases. The E3 ligase TNF receptor-associated factor 6 (TRAF6) acts as a key regulator bridging innate immunity, pro-inflammatory cytokines, and antigen receptors to the canonical NF-κB pathway. Structural analysis and point mutations have unraveled the essential role of TRAF6 binding to the E2-conjugating enzyme ubiquitin-conjugating enzyme E2 N (Ubc13 or UBE2N) to generate Lys63-linked ubiquitin chains for inflammatory and immune signal propagation. Genetic mutations disrupting TRAF6-Ubc13 binding have been shown to reduce TRAF6 activity and, consequently, NF-κB activation. However, to date, no small-molecule modulator is available to inhibit the TRAF6-Ubc13 interaction and thereby counteract NF-κB signaling and associated diseases. Here, using a high-throughput small-molecule screening approach, we discovered an inhibitor of the TRAF6-Ubc13 interaction that reduces TRAF6-Ubc13 activity both in vitro and in cells. We found that this compound, C25-140, impedes NF-κB activation in various immune and inflammatory signaling pathways also in primary human and murine cells. Importantly, C25-140 ameliorated inflammation and improved disease outcomes of autoimmune psoriasis and rheumatoid arthritis in preclinical in vivo mouse models. Hence, the first-in-class TRAF6-Ubc13 inhibitor C25-140 expands the toolbox for studying the impact of the ubiquitin system on immune signaling and underscores the importance of TRAF6 E3 ligase activity in psoriasis and rheumatoid arthritis. We propose that inhibition of TRAF6 activity by small molecules represents a promising novel strategy for targeting autoimmune and chronic inflammatory diseases.

AB - Constitutive NF-κB signaling represents a hallmark of chronic inflammation and autoimmune diseases. The E3 ligase TNF receptor-associated factor 6 (TRAF6) acts as a key regulator bridging innate immunity, pro-inflammatory cytokines, and antigen receptors to the canonical NF-κB pathway. Structural analysis and point mutations have unraveled the essential role of TRAF6 binding to the E2-conjugating enzyme ubiquitin-conjugating enzyme E2 N (Ubc13 or UBE2N) to generate Lys63-linked ubiquitin chains for inflammatory and immune signal propagation. Genetic mutations disrupting TRAF6-Ubc13 binding have been shown to reduce TRAF6 activity and, consequently, NF-κB activation. However, to date, no small-molecule modulator is available to inhibit the TRAF6-Ubc13 interaction and thereby counteract NF-κB signaling and associated diseases. Here, using a high-throughput small-molecule screening approach, we discovered an inhibitor of the TRAF6-Ubc13 interaction that reduces TRAF6-Ubc13 activity both in vitro and in cells. We found that this compound, C25-140, impedes NF-κB activation in various immune and inflammatory signaling pathways also in primary human and murine cells. Importantly, C25-140 ameliorated inflammation and improved disease outcomes of autoimmune psoriasis and rheumatoid arthritis in preclinical in vivo mouse models. Hence, the first-in-class TRAF6-Ubc13 inhibitor C25-140 expands the toolbox for studying the impact of the ubiquitin system on immune signaling and underscores the importance of TRAF6 E3 ligase activity in psoriasis and rheumatoid arthritis. We propose that inhibition of TRAF6 activity by small molecules represents a promising novel strategy for targeting autoimmune and chronic inflammatory diseases.

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