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Brenke, J.K. ; Popowicz, G.M. ; Schorpp, K.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.

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

J. Biol. Chem. 293, 13191-13203 (2018)
Verlagsversion Postprint DOI PMC
Open Access Gold
Constitutive NE-kappa B 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-kappa B 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, NE-kappa B activation. However, to date, no small-molecule modulator is available to inhibit the TRAF6-Ubc13 interaction and thereby counteract NF-kappa B 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-kappa B 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Nf-kappa B (nf-kb) ; Traf6 ; Ubc13 ; Autoimmunity ; Chemical Biology ; Drug Discovery ; Inflammation ; Protein-protein Interaction ; Psoriasis ; Rheumatoid Arthritis ; Small Molecule; Kappa-b; Rheumatoid-arthritis; Drug Discovery; Frequent Hitters; Ubiquitin; Activation; Malt1; Cells; Identification; Opportunities
Sprache
Veröffentlichungsjahr 2018
HGF-Berichtsjahr 2018
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Zeitschrift Journal of Biological Chemistry, The
Quellenangaben Band: 293, Heft: 34, Seiten: 13191-13203 Artikelnummer: , Supplement: ,
Verlag American Society for Biochemistry and Molecular Biology
Verlagsort 9650 Rockville Pike, Bethesda, Md 20814-3996 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Toxicology and Pharmacology (TOX)
Institute of Structural Biology (STB)
Research Unit Signaling and Translation (SAT)
Institute of Medicinal Chemistry (IMC)
Institute of Virology (VIRO)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
Immune Response and Infection
PSP-Element(e) G-505293-001
G-503000-001
G-509800-002
G-506300-001
G-502700-001
DOI 10.1074/jbc.RA118.002649
WOS ID WOS:000442730200018
Scopus ID 85052791392
PubMed ID 29950522
Erfassungsdatum 2018-07-04
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