TNFRSF6

TNFRSF6 is a gene that encodes the Fas receptor (CD95), a member of the tumor necrosis factor receptor superfamily. The Fas receptor is a cell-surface protein that plays a central role in the extrinsic pathway of programmed cell death, helping to regulate immune system homeostasis by promoting the deletion of activated or autoreactive cells and contributing to immune privilege in certain tissues.

The Fas receptor is a type I transmembrane glycoprotein. Its extracellular region contains three cysteine-rich domains that bind the Fas ligand, while the cytoplasmic region contains a death domain essential for signal transduction. The Fas ligand, encoded by TNFSF6, is typically expressed as a trimer and induces receptor trimerization upon binding.

Upon Fas ligand engagement, Fas receptors trimerize and recruit the adaptor protein FADD through death domain interactions. FADD then recruits and activates initiator caspases, notably caspase-8 or caspase-10, at the death-inducing signaling complex (DISC). Activation of these caspases initiates a cascade leading to apoptosis. In some cell types (type II cells), an amplification loop involving mitochondrial outer membrane permeabilization and Bid cleavage augments the apoptotic signal, enhancing cell death.

Fas signaling is tightly regulated. Expression of Fas and FasL is controlled by cellular activation and cytokines; negative regulation occurs via inhibitors such as c-FLIP, and soluble forms of Fas can act as decoys. Viral proteins and other factors can also modulate the pathway.

Clinically, mutations in TNFRSF6 or related pathway components can cause autoimmune lymphoproliferative syndrome (ALPS), characterized by impaired lymphocyte apoptosis, lymphadenopathy, and autoimmune manifestations. Dysregulated Fas signaling has been implicated in cancer, autoimmunity, and tissue injury, and targeted modulation of the Fas pathway has been explored in therapeutic research.