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Regulation of TNFR1 and CD95 Signalling by Receptor

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Regulation of TNFR1 and CD95 Signalling by Receptor PERS P ECTIVES Death-receptor signalling OPINION The TNF superfamily of cytokines com- prises 19 members and the corresponding Regulation of TNFR1 and TNFR superfamily includes 23 related receptors. A subgroup of this family includes the ‘death receptors’, TNFR1, CD95 signalling by receptor CD95, the TNF-related apoptosis-inducing ligand (TRAIL) receptors (TRAIL R1, also compartmentalization known as DR4; and TRAIL R2, also known as DR5), DR3, DR6 and p75NTR. These Stefan Schütze, Vladimir Tchikov and Wulf Schneider-Brachert receptors share a ‘death domain’, a conserved 80-amino-acid sequence in the cytoplasmic Abstract | The death receptors tumour-necrosis factor receptor-1 (TNFR1) and tail that is necessary for the direct activation CD95 (also known as FAS and APO-1) transduce signals that promote cell death by of the apoptotic programme by some of apoptosis. However, these receptors are also capable of inducing anti-apoptotic these receptors (TNFR1, CD95, TRAIL R1 signals through the activation of the transcription factor nuclear factor-κB (NF-κB) and TRAIL R2). TNF-induced apoptosis is or through activation of the proliferative mitogen-activated protein kinase (MAPK) mediated by the recruitment of the adaptor proteins TNFR-associated death-domain cascade. Recent findings reveal a role for receptor internalization and endosomal (TRADD) protein, FAS-associated death- trafficking in selectively transmitting the signals that lead either to apoptosis or to domain protein (FADD) and caspase-8 the survival of the cell. to the cytoplasmic death domain of the receptor7. CD95 and TRAIL receptors do not require TRADD for the recruitment of FADD Several biological responses, ranging from However, the regulation of receptor and caspase-8 (see BOX 2 for details)8–10. proliferation and differentiation to cell death, endocytosis and signal transduction, TRADD also functions as an assembly are mediated by ligand-triggered receptor as well as the linkage of compartmen- platform to diverge TNFR1 signalling from activation at the plasma membrane. The talization to selective biological outcomes the death domain; interaction of TRADD classic model of signal transduction involves in vivo, is still poorly understood. Whether with receptor-interacting protein (RIP) and cell-surface receptors that are activated signalling from endosomal compartments TNFR-associated factor-2 (TRAF2) leads to after the binding of a ligand and transmit generates a different biological response the activation of the survival transcription intracellular signals to generate secondary to signalling from the plasma membrane factor nuclear factor-κB (NF-κB) and to the messengers. The activation of many receptors remains to be determined3. In this context, induction of the c-Jun N-terminal kinase also triggers the accelerated endocytosis of recent findings concerning death-recep- (JNK) cascade7,11–13. ligand-receptor complexes. This suggests tor signalling provide novel insights into Earlier reports suggested that the forma- that endocytic vesicles are important sites for the physiological role of both receptor tion of a TNF-mediated apoptosis signalling organizing the recruitment of specific com- internalization and endosomal trafficking complex follows a different mechanism than ponents in the activated signalling cascade. in selectively transmitting signals that lead the mechanism that is activated by the CD95 Endocytosis has long been regarded solely as either to apoptosis or to the survival of ligand or TRAIL14,15. Micheau and Tschopp15 a mechanism to terminate signalling through the cell. proposed a model in which TNFR1 receptor internalization and subsequent lyso- signalling involves the assembly of two somal degradation. However, it has become ...endocytosis orchestrates molecularly and spatially distinct signalling clear that certain signalling pathways require cell signalling by coupling and complexes that sequentially activate NF-κB receptor internalization for full activation to integrating different cascades and caspases. Within a few minutes of TNF occur (for example, epidermal growth factor on the surface of endocytic binding, TNFR1 recruits TRADD, RIP1 and receptor, TRK, nerve growth factor receptor TRAF2 to form a signalling complex at the and insulin receptor). Emerging data suggest vesicles... cell surface (which is known as ‘complex I’) that endocytosis orchestrates cell signal- that activates NF-κB through recruitment of ling by coupling and integrating different In the following sections, we discuss the the inhibitor of κB (IκB) kinase (IKK) ‘sig- cascades on the surface of endocytic vesicles dichotomy of pro-apoptotic and anti- nalosome’. The signalosome is a high-molec- (reviewed in REFS 1–4). apoptotic signalling properties of the death ular-weight complex that comprises three Following receptor activation, receptors receptors tumour-necrosis factor recep- main proteins: two IκB kinases (IKK1 and and ligands can internalize from the cell tor-1 (TNFR1; also known as p55/60 and IKK2) and IKKγ (also known as NEMO). surface by various routes (summarized in CD120a) and CD95 (also known as FAS This model implies that, at later time points BOX 1). The best-characterized mechanism and APO-1). We highlight the early events and after TNFR1 internalization, RIP1, of endocytosis is clathrin-mediated endo- in the formation of ligand-activated recep- TRAF2 and TRADD become modified and cytosis. In addition, clathrin-independent tor complexes and we address the role of dissociate from the receptor. TRADD and/or pathways that involve cholesterol and post-translational modifications of CD95 RIP then bind to FADD, which results in the sphingolipid-enriched membrane domains in apoptosis signalling. We also discuss the recruitment of caspase-8 to a secondary sig- (lipid rafts) and special membrane invagi- role of internalization in determining the nalling complex within the cytosol (known nations (caveolae) also have important roles fate of the receptors and subsequently the as ‘complex II’). This complex subsequently in endocytosis (reviewed in REFS 5,6). specificity of signalling events. mediates apoptosis. natUre reViews | MOLECULAR CELL BIOLOGY VolUme 9 | AUGUst 2008 | 655 © 2008 Macmillan Publishers Limited. All rights reserved. PERS P ECTIVES Box 1 | Different mechanisms of receptor endocytosis known as p75/80 and CD120b). Both TNFRs contain four Cys-rich repeats in their extra- Lipid-raft-dependent internalization Clathrin-mediated cellular domains that mediate homophilic internalization Caveolin-mediated Clathrin- and caveolin- interactions in the absence of a ligand at Dynamin internalization independent internalization the pre-ligand assembly domain. These AP2 Cell Lipid raft homophilic interactions form homotrimers Clathrin membrane of each receptor type. Ligand binding to pre- Caveolin formed TNFR complexes induces intracellu- lar signal transduction. In contrast to TNFR1, Caveolae CCP TNFR2 does not contain a death domain and cannot transmit apoptotic signals. Role of internalization in TNFR1 signalling. Binding of TNF initiates the rapid clustering of TNFR1, followed by internalization of the Caveosome ligand-receptor complex via clathrin-coated Early pit formation18–22. In human endothelial CCV endosome cells, TNFR endocytosis has been linked to TNF-induced expression of NF-κB-regulated Early genes19; however, earlier reports suggest that endosome TNF-receptor internalization in other cell types might have a role in mediating TNF cytotoxicity23–25. trans-Golgi TNF activates two types of sphingo- vesicle myelinases — an endolysosomal acid sphingomyelinase (aSMase) and a mem- brane-bound neutral sphingomyelinase (nSMase)26. The lipid second messenger Nucleus Golgi Late endosome Lysosome ceramide, which is generated by sphingo- Receptors and ligands can be internalized from the cell surface by various routes. The first step in myelinases, is a potent pro-apoptotic media- clathrin-mediated endocytosis involves the selective recruitment of transmembrane receptors REFS 27,28 Nature Reviews | Molecular Cell Biology tor (reviewed in ). Conflicting data and their bound ligands into specialized membrane microdomains (known as clathrin-coated pits on the role of ceramide and sphingomyelinase (CCP); see figure). Several adaptor-protein complexes participate in this process, which is initiated in signalling have also been published27,29,30. by the binding of adaptor protein complex-2 (AP2) to the plasma membrane through its lipid- nSMase is activated via FAN (factor associ- binding domains. AP2 also binds to specific transport sequences within the intracellular sequence of the activated receptor. The best-characterized endocytosis motifs of cargo proteins are the ated with nSMase) and leads to the accumula- 31,32 Tyr-based YXXΦ motif (Y represents tyrosine, X any amino acid, and Φ a bulky hydrophobic amino tion of ceramide at the plasma membrane . acid) and dileucine-based motifs. Interaction of AP2 with the GTPase dynamin results in a ring The role of nSMase in TNF signalling remains formation around the neck of budding vesicles that leads to membrane fission and generation of unclear33. Activation of aSMase is dependent free clathrin-coated vesicles (CCVs). After uncoating during intracellular trafficking, CCVs fuse on TNFR1 internalization20,21 and is mediated with early endosomes and with trans-Golgi vesicles, from which the ligand-receptor complexes via the death domain of TNFR1 by the are sorted to various intracellular compartments, such as late endosomes
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