TRAF6 Phosphorylation Prevents Its Autophagic Degradation and Re-Shapes LPS-Triggered Signaling Networks

Julia Busch, Rita Moreno, Laureano de la Vega, Vera Vivian Saul, Susanne Bacher, Felix von Zweydorf, Marius Ueffing, Axel Weber, Christian Johannes Gloeckner, Uwe Linne, Michael Kracht, Michael Lienhard Schmitz (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
53 Downloads (Pure)


The ubiquitin E3 ligase TNF Receptor Associated Factor 6 (TRAF6) participates in a large number of different biological processes including innate immunity, differentiation and cell survival, raising the need to specify and shape the signaling output. Here, we identify a lipopolysaccharide (LPS)-dependent increase in TRAF6 association with the kinase IKKε (inhibitor of NF-κB kinase subunit ε) and IKKε-mediated TRAF6 phosphorylation at five residues. The reconstitution of TRAF6-deficient cells, with TRAF6 mutants representing phosphorylation-defective or phospho-mimetic TRAF6 variants, showed that the phospho-mimetic TRAF6 variant was largely protected from basal ubiquitin/proteasome-mediated degradation, and also from autophagy-mediated decay in autolysosomes induced by metabolic perturbation. In addition, phosphorylation of TRAF6 and its E3 ligase function differentially shape basal and LPS-triggered signaling networks, as revealed by phosphoproteome analysis. Changes in LPS-triggered phosphorylation networks of cells that had experienced autophagy are partially dependent on TRAF6 and its phosphorylation status, suggesting an involvement of this E3 ligase in the interplay between metabolic and inflammatory circuits.

Original languageEnglish
Article number3618
Number of pages20
Issue number14
Publication statusPublished - 19 Jul 2021


  • Autophagy
  • IKKε
  • Kinase activation
  • LPS
  • NF-κB
  • Phosphorylation
  • Signaling
  • TRAF6

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'TRAF6 Phosphorylation Prevents Its Autophagic Degradation and Re-Shapes LPS-Triggered Signaling Networks'. Together they form a unique fingerprint.

Cite this