APRIL and TACI interact with syndecan-1 on the surface of multiple myeloma cells to form an essential survival loop.
BLyS and APRIL share two receptors - transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA) - and BLyS binds to a third receptor, BAFF-R. We previously reported that TACI gene expression is a good indicator of a BLyS-binding receptor in human multiple myeloma cell lines (HMCLs), unlike BCMA, which is expressed by all HMCLs or BAFF-R which is typically not expressed by late-stage B cells. We hypothesised a link between APRIL and TACI through syndecan-1, similar to the situation reported for FGF and FGFR. We observed very strong binding of APRIL, but not BLyS, at the surface of all syndecan-1(+) HMCLs and primary multiple myeloma cells (MMC). All syndecan-1(+) HMCLs and MMC could also bind TACI-Fc, but not BCMA-Fc or BAFF-R-Fc molecules. Binding of APRIL or TACI-Fc was abrogated by heparin or cell pretreatment with heparitinase, which cleaves heparan sulfate chains. The growth factor activity of APRIL on MMC was also inhibited by heparin. Our data identify syndecan-1 as a co-receptor for APRIL and TACI at the cell surface of MMC, promoting the activation of an APRIL/TACI pathway that induces survival and proliferation in MMC.
Moreaux
Jérôme
J
CHU Montpellier, Institute of Research in Biotherapy, Montpellier, France.
Sprynski
Anne-Catherine
AC
Dillon
Stacey R
SR
Mahtouk
Karène
K
Jourdan
Michel
M
Ythier
Arnaud
A
Moine
Philippe
P
Robert
Nicolas
N
Jourdan
Eric
E
Rossi
Jean François
JF
Klein
Bernard
B
D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D005434:Flow Cytometry; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053668:Syndecan-1 / Q000378:metabolism*; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
C508241:SDC1 protein, human; D053668:Syndecan-1; C114631:TNFSF13 protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D006493:Heparin