Life and Death Decisions in the CD95 System: Main Proand Anti-Apoptotic Modulators

Abstract

Apoptosis is common to all multicellular organisms. Apoptosis can be triggered by the extrinsic (death receptor (DR)) or the intrinsic (mitochondrial) death pathways.CD95 (APO-1/Fas) is a prototypic member of the DR family. This review is focused on the mechanisms of CD95 (APO-1/Fas)-mediated apoptosis and the role in the apoptosisof the death effector domain (DED)-containing proteins: pro-apoptotic protein procaspase-8 and anti-apoptotic protein c-FLIP. Gaining insights into these processes willimprove our understanding of the pathogenesis of diseases such as cancer, autoimmunity and AIDS, and will open new approaches to rational treatment strategies.

Full Text

Introd uction : CD95 and CD95 signaling CD95 (also called APO-1; Fas; fas antigen; tumor necrosis factor receptor superfamily member 6, TN FRSF6 or apoptosis antigen 1, APT1) is a member of the death receptor (DR) family, a subfamily of the tumor necrosis factor receptor superfamily (1). All members of the DR family are characterized by a cytoplasmic region termed the Death Domain (DD) (2;3). DD are 80-100 amino acid long motifs involved in the transduction of the apoptotic signal. The DD belongs to the so-called ‘death domain-fold superfamily’. This superfamily comprises the death domain (DD), the death effector domain (DED), and the caspase recruitment domain (CARD). Each of these motifs interacts with other proteins through homotypic interactions. All members of the DD-fold superfamily are characterized by similar structures that comprise six or seven antiparallel amphipatic α-helices. Crosslinking of CD95 with its natural ligand, CD95L (CD178) (4), or with agonistic antibodies, such as anti-APO-1 (5), induces apoptosis in sensitive cells. The binding of CD95L or agonistic antibodies to CD95 leads to the formation of the receptor complex at the cellular membrane, which was named death-inducing signaling complex (DISC) (6). The DISC consists of oligomerized receptors, the DD-containing adaptor molecule FADD/MORT 1 (Fas-Associated Death Domain), procaspase-8 (FLICE , MACHα, Mch5), procaspase10, and the cellular FLICE -inhibitory proteins (c-FLIP) (Fig. 1) (7-9). The interactions between the molecules at the DISC are based on homotypic contacts. The DD of the receptor interacts with the DD of FADD, while the DED of FADD interacts with the N-terminal tandem DEDs of procaspases8, -10 and c-FLIP. As a result of DISC formation procaspase8 is activated at the DISC resulting in the formation of the active caspase-8. Caspase-8 cleaves and thereby activates downstream effector caspases-3, -6, and -7.