Release of a membrane-bound death domain by -secretase processing of the p75^NTR homolog NRADD

Neurotrophin receptor alike death domain protein (NRADD) is a death-receptor-like protein with a unique ectodomain and an intracellular domain homologous to p75^NTR. Expression of NRADD results in apoptosis, but only in certain cell types. This paper characterizes the expression and proteolytic processing of the mature 55 kDa glycoprotein. N-terminally truncated NRADD is processed by a -secretase activity that requires presenilins and has the same susceptibility to -secretase inhibitors as the secretion of amyloid (A). The ectodomain of endogenous NRADD is shed by activation of metalloproteinases. Inhibitor studies provide evidence that NRADD is cleaved in two steps typical of regulated intramembrane proteolysis (RIP). Inhibition of -secretase abrogates both the production of the soluble intracellular domain of NRADD and the appearance of NRADD in subnuclear structures. Thus, solubilized death domains with close homology to p75^NTR might have a nuclear function. Furthermore, presenilin deficiency leads to abnormally glycosylated NRADD and overexpression of presenilin 2 inhibits NRADD maturation, which is dependent on the putative active site residue D366 but not on -secretase activity. Our results demonstrate that NRADD is an additional -secretase substrate and suggest that drugs against Alzheimer's disease will need to target -secretase in a substrate-specific manner.