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

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

  • J Biol Chem. 2018 Aug 24;293(34):13191-13203. doi: 10.1074/jbc.RA118.002649.
Jara K Brenke 1,  Grzegorz M Popowicz 2 3,  Kenji Schorpp 1,  Ina Rothenaigner 1,  Manfred Roesner 4,  Isabel Meininger 5,  Cédric Kalinski 6,  Larissa Ringelstetter 1,  Omar R'kyek 7 8,  Gerrit Jürjens 7 8,  Michelle Vincendeau 5 9,  Oliver Plettenburg 7 8,  Michael Sattler 2 3,  Daniel Krappmann 5,  Kamyar Hadian 10
Affiliations

Affiliations

  • 1 From the Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology.
  • 2 the Institute of Structural Biology.
  • 3 the Center for Integrated Protein Science Munich at Department Chemie, Technical University of Munich, Garching 85747, Germany.
  • 4 mroe-consulting, 65817 Eppstein, Germany, and.
  • 5 the Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology.
  • 6 Innovation Management.
  • 7 the Institute of Medicinal Chemistry, and.
  • 8 the Institute of Organic Chemistry, Leibnitz Universität Hannover, 30167 Hannover, Germany.
  • 9 the Institute of Virology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 10 From the Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, kamyar.hadian@helmholtz-muenchen.de.
PMID: 29950522 DOI: 10.1074/jbc.RA118.002649
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

NF-kappaB; TRAF6; Ubc13; autoimmunity; chemical biology; drug discovery; inflammation; protein-protein interaction; psoriasis; rheumatoid arthritis; small molecule.

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