Inhibition of death receptor signals by cellular FLIP

Abstract

The widely expressed protein Fas is a member of the tumour necrosis factor receptor family which can trigger apoptosis¹. However, Fas surface expression does not necessarily render cells susceptible to Fas ligand-induced death signals¹,², indicating that inhibitors of the apoptosis-signalling pathway must exist. Here we report the characterization of an inhibitor of apoptosis, designated FLIP (for FLICE-inhibitory protein), which is predominantly expressed in muscle and lymphoid tissues. The short form, FLIP_S, contains two death effector domains and is structurally related to the viral FLIP inhibitors of apoptosis³, whereas the long form, FLIP_L, contains in addition a caspase-like domain in which the active-centre cysteine residue is substituted by a tyrosine residue. FLIP_S and FLIP_L interact with the adaptor protein FADD⁴,⁵ and the protease FLICE⁶,⁷, and potently inhibit apoptosis induced by all known human death receptors¹. FLIP_L is expressed during the early stage of T-cell activation, but disappears when T cells become susceptible to Fas ligand-mediated apoptosis. High levels of FLIP_L protein are also detectable in melanoma cell lines and malignant melanoma tumours. Thus FLIP may be implicated in tissue homeostasis as an important regulator of apoptosis.