Association between Presenilin-1 and TRAF6 modulates regulated intramembrane proteolysis of the p75NTR 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-kappaB 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).
Powell
James C
JC
Signal Transduction Laboratory, Biochemistry Department, University College Cork, Cork, Ireland.
Twomey
Ciara
C
Jain
Raunak
R
McCarthy
Justin V
JV
D000595:Amino Acid Sequence; D000818:Animals; D002461:Cell Line, Transformed; D003720:Densitometry / Q000379:methods; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D053764:Presenilin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011392:Proline / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D054875:Ubiquitination / Q000502:physiology
D053764:Presenilin-1; D020800:Receptor, Nerve Growth Factor; D048029:TNF Receptor-Associated Factor 6; D018698:Glutamic Acid; D011392:Proline