Sequential processing of the transmembrane chemokines CX3CL1 and CXCL16 by α- and γ-secretases

• Published in: Biochemical and biophysical research communications Vol. 358; no. 1; pp. 233 - 240
• Main Authors: Schulte, A., Schulz, B., Andrzejewski, M.G., Hundhausen, C., Mletzko, S., Achilles, J., Reiss, K., Paliga, K., Weber, C., Rose John, S., Ludwig, A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.06.2007
• Subjects: ADAM Proteins - antagonists & inhibitors; ADAM Proteins - metabolism; ADAM10 Protein; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Cell Line; Cell migration; Chemokine CX3CL1; Chemokine CXCL16; Chemokines; Chemokines, CX3C - metabolism; Chemokines, CXC - metabolism; Cloning, Molecular; Humans; Inflammation; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; Metalloproteinases; Presenilin-1 - genetics; Presenilin-1 - metabolism; Presenilin-2 - genetics; Presenilin-2 - metabolism; Proteasome Endopeptidase Complex - metabolism; Protein Structure, Tertiary; Receptors, Scavenger - metabolism; Regulated intramembrane proteolysis; Secretases; Shedding; Shedding; Secretases; Regulated intramembrane proteolysis; Inflammation; Metalloproteinases; Chemokines; Cell migration
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2007.04.100

The chemokines CX3CL1/Fractalkine and CXCL16 are expressed as transmembrane molecules and can mediate cell–cell-adhesion. By proteolytic processing, CX3CL1 and CXCL16 are released from the cell surface by proteolytic shedding resulting in the generation of soluble chemoattractants. This ectodomain release is mediated by the α-secretase-like activity of the two disintegrins and metalloproteinases ADAM10 and ADAM17. Using CX3CL1 and CXCL16 constructs C-terminally fused to two Z-domains of Protein A (2Z-tag) we detect C-terminal fragments (CTFs) of both chemokines resulting from ADAM10-mediated cleavages at multiple sites as examined by inhibitor studies. Furthermore, inhibitor studies as well as genetic studies using presenilin 1/2-deficient cell lines suggest the involvement of γ-secretase-but not β-secretase-like activity in the processing of transmembrane chemokines. The combination of α- and γ-secretase and proteasomal inhibitors points towards a sequential processing of transmembrane chemokines by first ADAM10 and then γ-secretases and possible further degradation. This proteolytic processing cascade of transmembrane chemokines is similar to that described for Notch and E-cadherin where CTFs generated by γ-secretase serve as intracellular signal transmitters.