SorLA Signaling by Regulated Intramembrane Proteolysis

Abstract

The single-transmembrane receptor SorLA/LR11 contains binding domains typical for lipoprotein receptors and a VPS10 domain, which binds the neuropeptide head-activator. This undecapeptide enhances proliferation of neuronal precursor cells in a SorLA-dependent manner. Using specific inhibitors we found previously that head activator activates shedding of SorLA by the metalloprotease TACE close to the transmembrane domain releasing the large extracellular part of the receptor. Here we show that the remaining COOH-terminal membrane fragment of SorLA is processed by ␥-secretase. Inhibition of ␥-secretase by specific inhibitors or overexpression of dominant negative presenilin mutants and knock out of the presenilin genes led to accumulation of the SorLA membrane fragment and also of full-length SorLA in the membrane. In an in vitro assay we observed the ␥-secretase-dependent release of the two soluble cleavage products, the SorLA cytoplasmic domain and the SorLA ␤-peptide. These processing steps are reminiscent of a novel signaling pathway that has been described for the notch receptor. Here, the notch cytoplasmic domain is released into the cytoplasm by the ␥-secretase and migrates to the nucleus where it acts as a transcriptional regulator. In parallel we found that a fusion protein of the released cytoplasmic tail of SorLA with EGFP located to the nucleus only if the nuclear localization signal of SorLA was intact. In a reporter gene assay the cytoplasmic domain of SorLA acted as a transcriptional activator indicating that SorLA might directly regulate transcription after activation by ␥-secretase.

Brain-Derived Neurotrophic Factor Reduces Amyloidogenic Processing through Control of SORLA Gene Expression

“…Application of DAPT blocked ␥-secretase activity almost completely as confirmed by a massive reduction in A␤ 40 production in this assay (CTRL: 100 Ϯ 6.9% A␤ 40 ; DAPT treatment: 25.9 Ϯ 3.4% A␤ 40 ). In line with previous reports (Böhm et al, 2006), inhibition of ␥-secretase activity increased Sorla expression, likely by reducing the amount of SORLA ICD that represses the endogenous Sorla promoter (Fig. 10, lane 1).…”

“…For example, the intracellular domain (ICD) of SORLA is released by ␥-secretasemediated cleavage (Nyborg et al, 2006) and acts as repressor of SORLA gene transcription (Böhm et al, 2006). Thus, BDNF may block ␥-secretase activity, thereby reducing the amount of inhibitory SORLA ICD produced.…”

SorLA Complement-type Repeat Domains Protect the Amyloid Precursor Protein against Processing

“…The ectodomain of SorLA can be released by a metalloprotease with ␣-secretase activity (63,64), and SorLA is processed by ␥-secretase activity (65,66) as well as proposed to be a substrate for BACE1 (67). Therefore, SorLA could potentially be a competitive substrate for the enzymes responsible for APP cleavage, suggesting one mechanism for how SorLA expression might inhibit APP proteolysis.…”

Interleukin-1 Receptor Type 1 Is a Substrate for γ-Secretase-dependent Regulated Intramembrane Proteolysis

“…We next addressed the possibility that the IL-1R1 CTF, derived from PMA-induced ectodomain shedding, is subject to ␥-secretase cleavage. Independent studies have shown that synthetic ␥-secretase inhibitors enhance the accumulation of substrate CTFs by inhibiting ␥-secretase-mediated turnover and generation of ICDs (29,52). HEK293T cells were transiently transfected with empty vector (1st lane) or a plasmid encoding human IL-1R1, and cell cultures were subsequently treated with either PMA, the ␥-secretase inhibitor, XIX (68), or both (Fig.…”

“…Additionally, TNF-␣-converting enzyme mediates a proteolytic cleavage event in the proximal extracellular domain of numerous other type 1 membrane proteins, including amyloid precursor protein, Jagged, Delta, pro-TNF-␣, the TNF receptors, IL-1R2, IL-2-␣ receptor, IL-6 receptor, Notch, p75 neurotrophin receptor (p75 NTR ), and ErbB4 (18, 24 -32). Some of these proteins undergo a subsequent intramembrane cleavage event within the membrane-anchored C-terminal fragment (CTF) to generate soluble intracellular domains (ICD) (27)(28)(29)(30)(31)(32)(33)(34). This cleavage event is referred to as regulated intramembrane proteolysis (RIP) (35) and involves the activity of the presenilin-dependent ␥-secretase protease, which was initially characterized because of its involvement in the cleavage of amyloid precursor protein and generation of A␤ (36 -39).…”