CD95

CD95, also known as Fas receptor or TNFRSF6, is a cell surface receptor of the death receptor family that plays a key role in regulating programmed cell death. It is encoded by the FAS gene (also called TNFRSF6) on chromosome 10 in humans. The extracellular region contains three cysteine-rich domains that bind Fas ligand (FasL), while its intracellular region contains a death domain that recruits adaptor proteins to initiate signaling.

CD95 is a type I transmembrane protein widely expressed, with notable abundance in T cells, B cells, and other cells of the immune system, as well as various tissues. FasL is primarily expressed on activated T cells and natural killer cells, and exists in membrane-bound and soluble forms. Binding of FasL to CD95 promotes receptor trimerization and assembly of the death-inducing signaling complex (DISC), which includes FADD and procaspase-8 or -10, leading to caspase activation and apoptosis. In addition to the canonical extrinsic apoptotic pathway, CD95 signaling can engage non-apoptotic pathways such as NF-κB and MAPK under certain conditions, and can be modulated by regulators like c-FLIP.

Physiological roles of CD95 include immune system development, peripheral and central tolerance, and elimination of harmful or autoreactive cells. Dysregulation of Fas signaling is linked to autoimmune diseases, immunodeficiency, and cancer. Mutations in FAS cause autoimmune lymphoproliferative syndrome (ALPS). In cancer, CD95 signaling can be irregular, contributing to immune evasion or, in some contexts, to tumor cell death. Therapeutically, activating CD95 has been explored but faced challenges such as hepatotoxicity; strategies continue to explore selective engagement and context-dependent outcomes.