Sequential processing of the transmembrane chemokines CX3CL1 and CXCL16 by alpha- and gamma-secretases.
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.
Schulte
A
A
Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
Schulz
B
B
Andrzejewski
M G
MG
Hundhausen
C
C
Mletzko
S
S
Achilles
J
J
Reiss
K
K
Paliga
K
K
Weber
C
C
John
S Rose
SR
Ludwig
A
A
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D054428:Chemokine CX3CL1; D000075743:Chemokine CXCL16; D020523:Chemokines, CX3C / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism*; D003001:Cloning, Molecular; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051116:Receptors, Scavenger / Q000378:metabolism*
C515538:CX3CL1 protein, human; C423727:CXCL16 protein, human; D054428:Chemokine CX3CL1; D000075743:Chemokine CXCL16; D020523:Chemokines, CX3C; D019743:Chemokines, CXC; D008565:Membrane Proteins; D053764:Presenilin-1; D053766:Presenilin-2; D051116:Receptors, Scavenger; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D046988:Proteasome Endopeptidase Complex