TNF-related apoptosis-inducing ligand (TRAIL), also called apoptosis 2 ligand (Apo2L) for its similarity in sequence, structure, and function to Fas Ligand/Apo1L, is a 33-35 kDa type II transmembrane glycoprotein of the tumor necrosis factor superfamily, designated TNFSF10. Mouse TRAIL cDNA encodes a 17 amino acid (aa) N-terminal intracellular domain, a 20 aa transmembrane domain and a 253 aa extracellular domain. Like most TNF family members, TRAIL is bioactive as a homotrimer. Unlike other TNF family members, a zinc ion complexed by human Cys 230 (mouse Cys 240) of each of the three monomers is critical for structural stability. Either transmembrane or cysteine protease-released soluble sTRAIL induce apoptosis of many transformed cell lines, but rarely of normal cells. Accordingly, TRAIL is suggested to have a role in tumor surveillance. Mice with genetically disrupted TRAIL have defective thymocyte apoptosis, creating faulty negative selection and some increased susceptibility to induced autoimmune diseases. In humans, TRAIL controls apoptosis of erythrocyte precursors and sTRAIL is inversely correlated with hemoglobin. TRAIL transcripts are constitutively expressed in a variety of human (and presumably mouse) tissues and mononuclear cells.