TY  - JOUR
AU  - Busch, Julia
AU  - Moreno, Rita
AU  - de la Vega, Laureano
AU  - Saul, Vera Vivian
AU  - Bacher, Susanne
AU  - Zweydorf, Felix
AU  - Ueffing, Marius
AU  - Weber, Axel
AU  - Gloeckner, Christian Johannes
AU  - Linne, Uwe
AU  - Kracht, Michael
AU  - Schmitz, Michael Lienhard
TI  - TRAF6 Phosphorylation Prevents Its Autophagic Degradation and Re-Shapes LPS-Triggered Signaling Networks.
JO  - Cancers
VL  - 13
IS  - 14
SN  - 2072-6694
CY  - Basel
PB  - MDPI
M1  - DZNE-2021-00863
SP  - 3618
PY  - 2021
AB  - 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.
KW  - IKKε (Other)
KW  - LPS (Other)
KW  - NF-κB (Other)
KW  - TRAF6 (Other)
KW  - autophagy (Other)
KW  - kinase activation (Other)
KW  - phosphorylation (Other)
KW  - signaling (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34298830
C2  - pmc:PMC8303406
DO  - DOI:10.3390/cancers13143618
UR  - https://pub.dzne.de/record/155695
ER  -