Details
| Original language | English |
|---|---|
| Pages (from-to) | 13191-13203 |
| Number of pages | 13 |
| Journal | Journal of Biological Chemistry |
| Volume | 293 |
| Issue number | 34 |
| Early online date | 27 Jun 2018 |
| Publication status | Published - 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
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Biochemistry, Genetics and Molecular Biology(all)
- Cell Biology
Sustainable Development Goals
Cite this
- Standard
- Harvard
- Apa
- Vancouver
- BibTeX
- RIS
In: Journal of Biological Chemistry, Vol. 293, No. 34, 08.2018, p. 13191-13203.
Research output: Contribution to journal › Article › Research › peer review
}
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.
KW - Animals
KW - Arthritis, Rheumatoid/drug therapy
KW - Autoimmune Diseases/drug therapy
KW - HEK293 Cells
KW - High-Throughput Screening Assays
KW - Humans
KW - Inflammation/drug therapy
KW - Intracellular Signaling Peptides and Proteins
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Protein Interaction Maps
KW - Psoriasis/drug therapy
KW - Small Molecule Libraries/pharmacology
KW - TNF Receptor-Associated Factor 6/antagonists & inhibitors
KW - Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/antagonists & inhibitors
KW - Ubiquitin-Conjugating Enzymes/antagonists & inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85052791392&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA118.002649
DO - 10.1074/jbc.RA118.002649
M3 - Article
C2 - 29950522
VL - 293
SP - 13191
EP - 13203
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 34
ER -