TRICK2, A NEW ALTERNATIVELY SPLICED RECEPTOR THAT TRANSDUCES THE CYTOTOXIC SIGNAL FROM TRAIL

A subset of the tumour necrosis factor (TNF) receptor family contain a conserved intracellular motif, the death domain. Engagement of these receptors by their respective ligands initiates a signalling cascade t hat rapidly leads to cell death by apoptosis, We have cloned a new mem ber of this family, TRICK2, the TRAIL (TNF-related apoptosis-inducing ligand) receptor inducer of cell killing 2. TRICK2 is expressed in a n umber of cell types, and to particularly high levels in lymphocytes an d spleen, Two isoforms of the TRICK2 mRNA are generated by alternative pre-mRNA splicing and differ by a 29 amino-acid extension to the extr acellular domain. Overexpression of TRICK2 rapidly induced apoptosis i n 293T cells; this induction was dependent upon the presence of the de ath domain of TRICK2, Using a soluble molecule containing the TRICK2 e xtracellular domain, we demonstrated that TRICK2, like DR4 [1], is a r eceptor for TRAIL/APO-2L [2,3] and could inhibit TRAIL-induced killing of lymphocyte lines, such as the Jurkat T-cell line, TRAIL is upregul ated upon lymphocyte activation, as is the intensively studied ligand for Fas, Fast [4], TRAIL and its receptors might therefore provide ano ther system for the regulation of lymphocyte selection and proliferati on, as well as providing an additional weapon in the armoury of cytoto xic lymphocytes.