The naturally processed CD95L elicits a c-yes/calcium/PI3K-driven cell migration pathway

Area of Science:

• Immunology
• Cell Biology
• Molecular Signaling

Background:

• Soluble CD95L (CD95 Ligand) is elevated in chronic inflammatory disorders.
• Naturally processed CD95L acts as an apoptotic antagonist, unlike its membrane-bound counterpart.
• Previous studies used chimeric CD95Ls, not reflecting naturally processed forms.

Purpose of the Study:

• To investigate the biological effects of metalloprotease-cleaved CD95L (cl-CD95L) on activated T-lymphocytes.
• To elucidate the signaling mechanisms underlying cl-CD95L-induced cell migration.
• To understand the role of cl-CD95L in the context of systemic lupus erythematosus (SLE).

Main Methods:

• Confocal microscopy to observe CD95 capping during cell migration.
• Cell migration assays including wound healing, Boyden Chamber, and endothelial transmigration.
• Analysis of signaling pathways involving c-yes, Ca²⁺, and PI3K.

Main Results:

• Cleaved CD95L (cl-CD95L) promotes the formation of migrating pseudopods with capped CD95.
• cl-CD95L enhances T-lymphocyte migration through a c-yes/Ca²⁺/PI3K signaling pathway.
• A novel CD95-containing complex, the Motility-Inducing Signaling Complex (MISC), is involved in cl-CD95L-driven migration.

Conclusions:

• Metalloprotease-cleaved CD95L (cl-CD95L) actively promotes immune cell migration.
• The c-yes/Ca²⁺/PI3K pathway and the MISC complex are crucial for cl-CD95L-induced migration.
• Elevated cl-CD95L in inflammatory conditions like SLE may contribute to tissue damage by facilitating immune cell infiltration.