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FLIP and the Death Effector Domain Family Oncogene (2008) 27, 6216–6227 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc REVIEW FLIP and the death effector domain family JW Yu and Y Shi Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ, USA Death effector domains (DEDs) are protein interaction and stress that impinge on the mitochondria or modules found in a number of proteins known to regulate ‘extrinsically’ from extracellular ligands that activate apoptosis from death receptors. The core DED family death receptors at the cell surface. In either scenario, members that orchestrate programmed cell death from each pathway critically relies on the action of a family of death receptors include the adaptor protein FADD, the cysteine proteases known as caspases to initiate and initiator caspases procaspases-8 and -10 and the regulatory execute the cell death process through a two-step protein c-FLIP. Through homotypic DED interactions, cascade (Riedl and Shi, 2004). In the apoptotic these proteins assemble into the death-inducingsignaling proteolytic cascade, the initiator caspases (caspases-2, complex (DISC) to regulate initiator caspase activation -8, -9 and -10) cleave and consequently activate the and launch the apoptotic proteolytic cascade. A consider- effector caspases (caspases-3, -6 and -7), and the effector able body of evidence, however, is revealingthat the same caspases in turn cleave a large array of substrates to core group of DED-containing proteins also paradoxically dismantle and package the cell into apoptotic bodies. promotes survival and proliferation in lymphocytes and Activation of initiator caspases for both the intrinsic possibly other cell types. This review delves into recent and extrinsic pathways is a crucial regulatory step in findings regarding these two opposing functional aspects of inducing cell death and is achieved through adaptor- the core DED proteins. We discuss the current effort induced oligomerization (Bao and Shi, 2007). Assembly expandingour structural and biochemical view of how of the activating platform is mediated by protein–protein DED proteins assemble into the DISC to fully activate interactions driven by small hexa-helical domains that initiator caspases and execute cell death, and finally we include the caspase recruitment domain (CARD), the examine details linkingthe same proteins to proliferation death domain (DD) and the death effector domain and describe how this outcome might be achieved through (DED). These structurally conserved domains are restricted activation of initiator caspases. members of the DD superfamily, and within this large Oncogene (2008) 27, 6216–6227; doi:10.1038/onc.2008.299 group, the DD and DED subfamilies propagate apopto- tic and sometimes proliferative signals from death Keywords: apoptosis; extrinsic cell death; caspase-8; receptors in the extrinsic cell death pathway. Although DED; FLIP; NF-kB the DD is dispersed in a wide array of proteins (32 in total in humans) involved in multiple pathways, the DED is predominantly confined to eight proteins that dictate cellular fate from death receptors and possibly other locations (Figures 1 and 2) (Reed et al., 2004). In Introduction recent years, considerable interest has centered on three groups of DED family members, including FADD, Apoptosis is a tightly regulated cell death process procaspases-8/10 and c-FLIP (Long, Short and Raji), actively implemented to ensure proper development and much has been uncovered in the way they assemble during the early stages of life and homeostasis through- through homotypic DED interactions to implement the out the adulthood of all multicellular organisms apoptotic program. Perhaps most interesting of all, a (Rathmell and Thompson, 2002; Danial and Kors- collective body of research is beginning to establish that meyer, 2004). In humans, defects in this cell death the exact same core group of proteins that implement cell program resulting from insufficient or excessive apop- death (FADD, procaspases-8/10 and c-FLIP (L, S and tosis provokes a number of diseases, including auto- R)) can also work together to promote proliferative and immunity, cancer and neurodegenerative disorders survival signals in remarkable ways. Rather than (Hanahan and Weinberg, 2000; Vauxand Flavell, surveying the DED family as a whole, we focus our 2000; Yuan and Yankner, 2000; Green and Evan, attention to these recent developments in this review. 2002). This conserved cellular suicide program is initiated either ‘intrinsically’ through cellular insults Death receptors Correspondence: Dr JW Yu or Professor Y Shi, Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544, USA. As part of the tumor necrosis factor receptor super- E-mails: [email protected] or [email protected] family, the death receptor family so far consists of eight FLIP and the death effector domain family JW Yu and Y Shi 6217 members that possess an extracellular domain consisting and El-Deiry, 2003; Wajant, 2003). Of these identified of up to five cysteine-rich repeats and an intracellular members, only signaling from TNFR1, Fas and TRAIL DD. These include TNFR1, CD95/Fas, DR3, TRAILR1/ (DR4 and DR5) receptors are reasonably well character- DR4, TRAILR2/DR5, DR6, EDAR and NGFR (Ozoren ized and they trigger cell death or in some cases proliferation from the cell surface under varying condi- tions. From a physiological standpoint, Fas-mediated cell death appears to be critical for immune system function by removing self-reacting B and T cells, down-sizing the population of activated lymphocytes after an immune response, restricting immune system access from privileged sites such as the eye and testes, and eliminating cancer cells and virally infected cells (Krammer, 2000; Curtin and Cotter, 2003). In humans, loss of Fas receptor function has been implicated in autoimmune disorders and correlated with cancers of immune cells (and other cell types). In addition to its role in cell death, Fas receptor signaling also has been shown to be critical for T-cell survival and proliferation (Peter et al., 2007). Along this line, the Fas receptor also elicits non-apoptotic signals in diverse tissue Figure 1 The human death effector domain (DED) family types outside the immune system (Peter et al., 2007), members. FADD, procaspases-8/10 and c-FLIP (L, S and R) are core components of the death-inducing signaling complex(DISC). participating in functions such as liver regeneration DEDD, DEDD2 and PEA-15 are not nearly as well characterized, (Desbarats and Newell, 2000) and neurite outgrowth of but nevertheless have also been implicated in regulating extrinsic sensory neurons (Desbarats et al., 2003). The function of cell death in addition to participating in other cellular functions. the TRAIL receptors, on the other hand, are less well PEA-15, when phosphorylated, inhibits death receptor-induced apoptosis through homotyptic DED interactions with FADD to understood, although a number of studies implicate these prevent the recruitment of procaspases-8 and -10 (Condorelli et al., receptors in immune system function as well (Ozoren and 1999; Renganathan et al., 2005). DEDD and DEDD2 conversely El-Deiry, 2003). Most studies have focused on their are thought to function in a proapoptotic manner by interacting anticancer function given the fact that TRAIL ligand with and targeting caspases-8 and -10 to the nucleus, where they has been shown to induce apoptosis in a wide range of might inhibit protein translation (Alcivar et al., 2003). Further details regarding DEDD, DEDD2 and PEA-15 are not discussed in human cancer cell lines, whereas exhibiting no apparent this review. There are also a handful of additional proteins (not adverse effect on normal cells (Walczak et al., 1999; Abe shown in the figure and are also not discussed in this review) that et al., 2000; Wang and El-Deiry, 2003). Apoptotic contain variant DEDs (vDEDs), which are thought to be mere signaling by TNFR1 is less common and activation of coiled-coil regions and nonclassical DED-like (DED-L) domains (Reed et al., 2004). Proteins that contain vDED include Bap31, this receptor appears to be more critical in proinflamma- BAR, Hip and Hippi. Proteins that contain DED-L include tory responses (Ashkenazi and Dixit, 1998; Ozoren and FLASH and Dap3. NLS, nuclear localization signal. El-Deiry, 2003). Figure 2 Sequence alignment of death effector domains (DEDs) from human and viral proteins. The top panel shows an alignment of the single DED found in FADD, DEDD, DEDD2 and PEA-15. The lower panels show an alignment for the tandem DEDs present in viral FLIPs (MC159 and KSHV (Kaposi’s sarcoma-associated herpesvirus)), c-FLIP, procaspase-8b (C8b) and procaspase-10 (C10). A stretch of sixto ten amino acids that resides between DED1 and DED2 (between a7a and a1b) of the tandem DEDs are omitted from the sequence alignments in the lower panels. Residues that comprise the conserved hydrophobic patch are highlighted in red. The highly conserved RXDL motif found in a6 is denoted in yellow. Secondary structural elements illustrated above the sequences are based on the structures of the FADD (DED) for the top panel and MC159 for the lower panels. Oncogene FLIP and the death effector domain family JW Yu and Y Shi 6218 Apoptosis mediated by assembly of DED-containing In this case, allosteric activation of the protease domain proteins of procaspase-8 is thought to occur through hetero- dimerization with the catalytically
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