FasFasL

Fas ligand (FasL), also known as CD95L, is a member of the tumor necrosis factor (TNF) superfamily that binds to the Fas receptor (CD95) to regulate cell death and immune function. FasL is a type II transmembrane glycoprotein predominantly expressed on cytotoxic T lymphocytes and natural killer cells, with a soluble form produced by proteolytic shedding in some contexts.

Mechanism: Ligation of Fas by FasL induces trimerization of the Fas receptor and assembly of the death-inducing signaling complex (DISC) via the death domain of Fas and the adaptor protein FADD. This recruits and activates caspase-8 and caspase-10, triggering a caspase cascade and leading to apoptotic cell death. In many cells, activation of the extrinsic pathway by FasL is the primary mechanism of cytotoxic lymphocyte–mediated killing of infected or malignant cells. In other cells, caspase-8 cleavage of Bid links Fas signaling to mitochondrial pathways, amplifying apoptosis. Fas signaling can also engage non-apoptotic pathways, including NF-κB and MAP kinases, depending on cellular context. When caspase-8 activity is inhibited, Fas signaling can promote necroptosis via RIPK1/RIPK3/MLKL, and bidirectional signaling (reverse signaling) can occur through FasL-expressing cells.

Physiological and clinical relevance: The Fas/FasL system is essential for immune surveillance and maintenance of peripheral tolerance and immune privilege. Dysregulation is associated with autoimmune disease, chronic inflammation, and liver pathology, and defects in FAS or FASLG cause autoimmune lymphoproliferative syndrome (ALPS). Tumor cells may manipulate this axis to escape immune destruction. Therapeutic strategies targeting Fas/FasL are under investigation in cancer and immune disorders.