Sequential processing of the transmembrane chemokines CX3CL1 and CXCL16 by alpha- and gamma-secretases |
| |
Authors: | Schulte A Schulz B Andrzejewski M G Hundhausen C Mletzko S Achilles J Reiss K Paliga K Weber C John S Rose Ludwig A |
| |
Institution: | Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany. |
| |
Abstract: | 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 alpha-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 gamma-secretase-but not beta-secretase-like activity in the processing of transmembrane chemokines. The combination of alpha- and gamma-secretase and proteasomal inhibitors points towards a sequential processing of transmembrane chemokines by first ADAM10 and then gamma-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 gamma-secretase serve as intracellular signal transmitters. |
| |
Keywords: | Chemokines Metalloproteinases Shedding Secretases Regulated intramembrane proteolysis Cell migration Inflammation |
本文献已被 ScienceDirect PubMed 等数据库收录! |