Projects per year
Abstract
ADP-heptose activates the protein kinase ALPK1 triggering TIFA phosphorylation at Thr9, the recruitment of TRAF6 and the subsequent production of inflammatory mediators. Here, we demonstrate that ADP-heptose also stimulates the formation of Lys63- and Met1-linked ubiquitin chains to activate the TAK1 and canonical IKK complexes, respectively. We further show that the E3 ligases TRAF6 and c-IAP1 operate redundantly to generate the Lys63-linked ubiquitin chains required for pathway activation, which we demonstrate are attached to TRAF6, TRAF2 and c-IAP1, and that c-IAP1 is recruited to TIFA by TRAF2. ADP-heptose also induces activation of the kinase TBK1 by a TAK1-independent mechanism, which require TRAF2 and TRAF6. We establish that ALPK1 phosphorylates TIFA directly at Thr177 as well as Thr9 in vitro. Thr177 is located within the TRAF6-binding motif and its mutation to Asp prevents TRAF6 but not TRAF2 binding, indicating a role in restricting ADP-heptose signalling. We conclude that ADP-heptose signalling is controlled by the combined actions of TRAF2/c-IAP1 and TRAF6.
Original language | English |
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Pages (from-to) | 2195-2216 |
Number of pages | 22 |
Journal | Biochemical Journal |
Volume | 479 |
Issue number | 20 |
Early online date | 13 Sept 2022 |
DOIs | |
Publication status | Published - 28 Oct 2022 |
Keywords
- Innate immunity
- ubiquitylation
- E3 ligase
- ALPK1
- ADP-heptose
- TIFA
- TRAF
- TAK1
- IKK
- TBK1
ASJC Scopus subject areas
- Molecular Biology
- Biochemistry
- Cell Biology
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Dive into the research topics of 'Co-ordinated control of the ADP-heptose/ALPK1 signalling network by the E3 ligases TRAF6, TRAF2/c-IAP1 and LUBAC'. Together they form a unique fingerprint.Projects
- 2 Finished
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The Molecular Mechanisms by which TRAF6 Regulates the Immune System
Cohen, P. (Investigator)
1/04/18 → 31/03/24
Project: Research
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Elucidation of Mechanisms that Restrict Activation of the Innate Immune System to Prevent Inflammatory and Autoimmune Diseases
Arthur, S. (Investigator) & Cohen, P. (Investigator)
1/04/18 → 31/03/23
Project: Research
Student theses
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Genetic and biochemical dissection of the ADP-heptose-ALPK1-TIFA innate immune signalling pathway
Snelling, T. (Author), Cohen, P. (Supervisor), 2023Student thesis: Doctoral Thesis › Doctor of Philosophy
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