Association between Presenilin-1 and TRAF6 modulates regulated intramembrane proteolysis of the p75NTR neurotrophin receptor |
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Authors: | James C. Powell Ciara Twomey Raunak Jain Justin V. McCarthy |
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Affiliation: | Signal Transduction Laboratory, Biochemistry Department, University College Cork, Cork, Ireland |
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Abstract: | The p75 neurotrophin receptor (p75NTR) 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, p75NTR was also shown to undergo presenilin-dependent, γ-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 γ-secretase cleavage of p75NTR. Additionally, we show that PS1-deficiency antagonizes NGF-induced I-κB degradation. Finally, we also show that p75NTR is a substrate for TRAF6-mediated ubiquitination and that TRAF6 E3 ligase activity is required for regulated intramembrane proteolysis of p75NTR. In summary, our data suggest that an NGF-induced association between PS1 and TRAF6 influences regulated intramembrane proteolysis of p75NTR. |
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Keywords: | p75 neurotrophin receptor γ-secretase presenilin regulated intramembrane proteolysis tumour necrosis factor receptor-associated factor 6 ubiquitination |
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