Coordinated control of the ADP-heptose/ALPK1 signalling network by the E3 ligases TRAF6, TRAF2/c-IAP1 and LUBAC

Tom Snelling, Natalia Shpiro, Robert Gourlay, Frederic Lamoliatte, Philip Cohen (Lead / Corresponding author)

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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 languageEnglish
Pages (from-to)2195-2216
Number of pages22
JournalBiochemical Journal
Volume479
Issue number20
Early online date13 Sep 2022
DOIs
Publication statusPublished - 28 Oct 2022

Keywords

  • Innate immunity
  • ubiquitylation
  • E3 ligase
  • ALPK1
  • ADP-heptose
  • TIFA
  • TRAF
  • TAK1
  • IKK
  • TBK1

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