Association between Presenilin-1 and TRAF6 modulates regulated intramembrane proteolysis of the p75(NTR) neurotrophin receptor

The p75 neurotrophin receptor (p75(NTR)) is a member of the tumour necrosis factor superfamily, which relies on the recruitment of cytosolic protein partners including the tumour necrosis factor receptor-associated factor 6 (TRAF6) E3 ubiquitin ligase to produce cellular responses. Recently, p75(NTR) was also shown to undergo presenilin-dependent, gamma-secretase-mediated regulated intramembrane proteolysis. In this study, we report the characterization of a highly conserved TRAF6-binding site (PxExxAr/Ac) in presenilin-1 (PS1) that mediates nerve growth factor (NGF)-induced association between PS1 and TRAF6. We demonstrate that disruption of this interaction between PS1 and TRAF6 inhibits TRAF6 autoubiquitination and gamma-secretase cleavage of p75(NTR). Additionally, we show that PS1-deficiency antagonizes NGF-induced I-kappa B degradation. Finally, we also show that p75(NTR) is a substrate for TRAF6-mediated ubiquitination and that TRAF6 E3 ligase activity is required for regulated intramembrane proteolysis of p75(NTR). In summary, our data suggest that an NGF-induced association between PS1 and TRAF6 influences regulated intramembrane proteolysis of p75(NTR).