Nonapoptotic functions of Fas/CD95 in the immune response

CD95 (also known as Fas) is a member of the tumor necrosis factor receptor (TNFR) superfamily. Its cognate ligand, CD95L, is implicated in immune homeostasis and immune surveillance. Mutations in this receptor are associated with a loss of apoptotic signaling and have been detected in an autoimmune disorder called autoimmune lymphoproliferative syndrome (ALPS) type Ia, which shares some clinical features with systemic lupus erythematosus (SLE). In addition, deletions and mutations of CD95 have been described in many cancers, which led researchers to initially classify this receptor as a tumor suppressor. More recent data demonstrate that CD95 engagement evokes nonapoptotic signals that promote inflammation and carcinogenesis. Transmembrane CD95L (m-CD95L) can be cleaved by metalloproteases, releasing a soluble ligand (s-CD95L). Soluble and membrane-bound CD95L show different stoichiometry (homotrimer versus multimer of homotrimers, respectively), which differentially affects CD95-mediated signaling through molecular mechanisms that remain to be elucidated. This review discusses the biological roles of CD95 in light of recent experiments addressing how a death receptor can trigger both apoptotic and nonapoptotic signaling pathways.