INHIBITION OF DEATH RECEPTOR SIGNALS BY CELLULAR FLIP

The widely expressed protein Fas is a member of the tumour necrosis fa ctor receptor family which fan trigger apoptosis(1). However, Fas surf ace expression does not necessarily render cells susceptible to Fas li gand-induced death signals(1,2), indicating that inhibitors of the apo ptosis-signalling pathway must exist. Here we report the characterizat ion of an inhibitor of apoptosis, designated FLIP (for FLICE-inhibitor y protein), which is predominantly expressed in muscle and lymphoid ti ssues. The short form, FLIPS, contains two death effector domains and is structurally related to the viral FLIP inhibitors of apoptosis(3), whereas the long form, FLIPL, contains in addition a caspase-like doma in in which the active-centre cysteine residue is substituted by a tyr osine residue. FLIPS and FLIPL interact with the adaptor protein FADD( 4,5) and the protease FLICE6,7, and potently inhibit apoptosis induced by all known human death receptors(1). FLIPL is expressed during the early stage of T-cell activation, but disappears when T cells become s usceptible to Fas ligand-mediated apoptosis. High levels of FLIPL prot ein are also detectable in melanoma cell lines and malignant melanoma tumours. Thus FLIP may be implicated in tissue homeostasis as an impor tant regulator of apoptosis.