title: The naturally processed CD95L elicits a c-yes/calcium/PI3K-driven cell migration pathway.
abstract: Patients affected by chronic inflammatory disorders display high amounts of soluble CD95L. This homotrimeric ligand arises from the cleavage by metalloproteases of its membrane-bound counterpart, a strong apoptotic inducer. In contrast, the naturally processed CD95L is viewed as an apoptotic antagonist competing with its membrane counterpart for binding to CD95. Recent reports pinpointed that activation of CD95 may attract myeloid and tumoral cells, which display resistance to the CD95-mediated apoptotic signal. However, all these studies were performed using chimeric CD95Ls (oligomerized forms), which behave as the membrane-bound ligand and not as the naturally processed CD95L. Herein, we examine the biological effects of the metalloprotease-cleaved CD95L on CD95-sensitive activated T-lymphocytes. We demonstrate that cleaved CD95L (cl-CD95L), found increased in sera of systemic lupus erythematosus (SLE) patients as compared to that of healthy individuals, promotes the formation of migrating pseudopods at the leading edge of which the death receptor CD95 is capped (confocal microscopy). Using different migration assays (wound healing/Boyden Chamber/endothelial transmigration), we uncover that cl-CD95L promotes cell migration through a c-yes/Ca²⁺/PI3K-driven signaling pathway, which relies on the formation of a CD95-containing complex designated the MISC for Motility-Inducing Signaling Complex. These findings revisit the role of the metalloprotease-cleaved CD95L and emphasize that the increase in cl-CD95L observed in patients affected by chronic inflammatory disorders may fuel the local or systemic tissue damage by promoting tissue-filtration of immune cells.
authors.affiliation: Université de Rennes-1, Rennes, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Tauzin
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chaigne-Delalande
authors.forename: Eric
authors.initials: E
authors.lastname: Selva
authors.forename: Nadine
authors.initials: N
authors.lastname: Khadra
authors.forename: Sophie
authors.initials: S
authors.lastname: Daburon
authors.forename: Cécile
authors.initials: C
authors.lastname: Contin-Bordes
authors.forename: Patrick
authors.initials: P
authors.lastname: Blanco
authors.forename: Jacques
authors.initials: J
authors.lastname: Le Seyec
authors.forename: Thomas
authors.initials: T
authors.lastname: Ducret
authors.forename: Laurent
authors.initials: L
authors.lastname: Counillon
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Moreau
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.forename: Pierre
authors.initials: P
authors.lastname: Vacher
authors.forename: Patrick
authors.initials: P
authors.lastname: Legembre
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D053222:Fas Ligand Protein / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011554:Pseudopodia / Q000502:physiology; D015398:Signal Transduction; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D053222:Fas Ligand Protein; D019014:fas Receptor; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases