SorLA signaling by regulated intramembrane proteolysis.
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 extra-cellular part of the receptor. Here we show that the remaining COOH-terminal membrane fragment of SorLA is processed by gamma-secretase. Inhibition of gamma-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 gamma-secretase-dependent release of the two soluble cleavage products, the SorLA cytoplasmic domain and the SorLA beta-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 gamma-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 gamma-secretase.
University Medical Center Hamburg-Eppendorf, Center of Experimental Medicine, Department of Biochemistry and Molecular Biology II: Molecular Cell Biology, Martinistrasse 52, D-20246 Hamburg, Germany.
Christopher
C
Böhm
Nicole M
NM
Seibel
Birgit
B
Henkel
Harald
H
Steiner
Christian
C
Haass
Wolfgang
W
Hampe
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals; D010455:Peptides / Q000737:chemistry; D053764:Presenilin-1; D021382:Protein Sorting Signals; D011973:Receptors, LDL / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
D026502:LDL-Receptor Related Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D019913:Nuclear Localization Signals; C508853:PSEN1 protein, human; D010455:Peptides; D053764:Presenilin-1; D021382:Protein Sorting Signals; D011973:Receptors, LDL; C102582:SORL1 protein, human; D049452:Green Fluorescent Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human