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Biochem. J. (2008) 413, e11–e12 (Printed in Great Britain) e11 doi:10.1042/BJ20081094 COMMENTARY CD95 ligation and intracellular membrane flow Roland REINEHR and Dieter HÄUSSINGER1 Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany Whereas ligation of the CD95 death receptor in the plasma membrane of so-called type I cells leads to a direct caspase 8-dependent activation of downstream effector caspases, mitochondrial amplification of caspase 8-derived signals is required in so-called type II cells in order to execute apoptotic cell death. In type I cells CD95L (CD95 ligand) binding to CD95 results in a ceramide-dependent formation of the DISC (death-inducing signalling complex) and caspase 8-dependent CD95 clustering in the plasma membrane, followed by an internalization of these multimeric-receptor–DISC complexes. In contrast, in the hepatocyte, a type II cell, the bulk of CD95 is stored intracellularly under resting conditions and only a few ‘sentinel’ CD95 receptors are present in the plasma membrane. However, their activation by CD95L is sufficient to trigger a caspase 8-dependent endosomal acidification and a ceramide-dependent trafficking of intracellularly stored CD95 to the plasma membrane, thereby amplifying CD95 activation. Thus, in both type I and type II cells, ceramide and CD95 receptor endo- and exo-cytosis are involved in CD95-mediated apoptosis, but apparently in different ways. This, however, is not the only effect of CD95 ligation on intracellular membrane flow in type II cells, and evidence has been presented that soon after CD95 ligation Golgi elements intermix caspase-dependently with mitochondria. In this issue of the Biochemical Journal, Matarrese et al. report another aspect on endocytosis in response to CD95 ligation in type II cells, namely a caspase-independent endocytosis with vesicle translocation to the mitochondrial compartment, suggestive of an interplay between both organelles in the sense of an ‘organelle scrambling’. Thus early effects of CD95 activation on intracellular membrane flow may be much more complex than previously thought, but much has still to be learned about signalling mechanisms and the role they play in apoptosis. CD95-mediated apoptosis is an important process with enormous physiological and pathophysiological impact and cell-typespecific features. Whereas in so-called type I cells, the CD95L (CD95 ligand)–CD95 (CD95 receptor) interaction is followed by formation of the DISC (death-inducing signalling complex) and caspase 8 activation, which is sufficient for activation of downstream effector caspases and execution of cell death, in socalled type II cells, the apical caspase signals require mitochondrial amplification for induction of apoptotic cell death [1]. This amplification is achieved by the caspase 8-dependent cleavage of Bcl-2-family members, e.g. Bid, which induce a loss of the MMP (mitochondrial membrane potential) and the release of proapoptotic factors such as cytochrome c, which finally trigger the activation of downstream ‘effector caspases’ [1]. It has been reported recently that, in type I cells, CD95L–CD95 ligation is followed by a ceramide-dependent DISC formation and subsequent caspase 8-dependent CD95 clustering at the plasma membrane which is then followed by an internalization of these multi-receptor–DISC conglomerates [2]. Interestingly, inhibition of CD95 internalization is followed by activation of alternative signalling cascades, i.e. activation of the proliferative ERK (extracellular-signal-regulated kinase) and NF-κB (nuclear factor κB) pathway [2], indicating that, depending on the signalling context, the CD95L–CD95 interaction can couple to both cell death and cell proliferation. Whereas in most type I cells the bulk of CD95 is already located at the plasma membrane under control conditions, it has been reported, for at least some type II cells, that both CD95Ldependent [3] and -independent activation of the CD95 system [4] involves substantial trafficking of the CD95 receptor from the cellular interior to the plasma membrane. In prototypical type II cells, such as rat hepatocytes, the bulk of CD95 is stored intracellularly, with only very few ‘sentinel’ receptors at the plasma membrane. Their ligation triggers a caspase 8-dependent rise of the intracellular chloride concentration, leading to an endosomal acidification, subsequent activation of acidic sphingomyelinase and ceramide formation [5]. These events occur within seconds after CD95 ligation and trigger a PKCζ (protein kinase Cζ )-mediated activation of NADPH oxidase with subsequent formation of ROS (reactive oxygen species) [5]. This ROS response then leads to a Yes-mediated EGFR (epidermal growth factor receptor) transactivation and a JNK (c-Jun N-terminal kinase)-dependent association of the CD95 with the EGFR, which allows for EGFR-mediated CD95 tyrosine phosphorylation [3]. CD95 tyrosine phosphorylation is required for further recruitment of CD95 to the CD95–EGFR complex (oligomerization) and subsequent trafficking of the CD95–EGFR complex to the plasma membrane, where DISC formation and substantial caspase 8 activation occurs [3]. Inhibition of the vacuolar-type H+ ATPase by bafilomycin abolishes CD95L-induced endosomal acidification and apoptosis induction [5]. Exocytic recruitment of CD95–EGFR complexes to the plasma membrane in type II cells, however, is only one aspect of the early alterations of intracellular membrane flow induced by CD95 ligation. Evidence has been presented for a complex mixing of Golgi elements with mitochondria and a caspase-dependent outward movement of secretory endomembranes [6]. In this issue of the Biochemical Journal, Matarrese et al. [7] now report on another role of endosomes in CD95-dependent type II cell death by demonstrating an induction of endocytosis in the human lymphoblastoid T cell line CEM in response to CD95 ligation. Transmission electron microscopy and immunogold 1 Key words: apoptosis, cell volume, endosomal compartment, endocytosis, CD95/Fas/APO-1 receptor, CD95 trafficking, mitochondrial amplification, mitochondrial membrane potential (MMP), type II cell. To whom correspondence should be addressed (email [email protected]). c The Authors Journal compilation c 2008 Biochemical Society e12 R. Reinehr and D. Häussinger labelling studies on endocytosed BSA revealed not only an increase of endocytotic vacuoles, but also provided evidence for a scrambling of such vesicles with mitochondrial membranes. This cross-talk between endosomal and mitochondrial compartments was accompanied by a loss of the MMP and apoptosis execution. This cell remodelling was sensitive to monensin and was absent not only after induction of receptor-independent cell death with staurosporine, but also in cells selected for multidrug resistance. As shown in sucrose gradient experiments, these endocytotic vesicles probably did not contain CD95 receptors. In contrast with the reported CD95–DISC internalization upon the CD95L– CD95 interaction in type I cells [2] and the scrambling between Golgi-derived and mitochondrial membranes in type II cells [6], the reported increase in type II cell endocytosis was caspaseindependent. From these results the authors concluded that the endosomal/mitochondrial ‘organelle cross-talk’ may play a key role in both propagation and amplification of CD95-mediated apoptosis. Thus CD95 ligation in type II cells induces early and complex alterations in intracellular membrane flow, involving endosomes, mitochondria and Golgi, which may contribute to the induction of cell death. The mechanisms and signalling pathways towards CD95-triggered endocytosis, however, remain unclear. Ceramide is formed very rapidly in response to CD95 ligation and may be a key compound in this respect, because there is evidence for its involvement in CD95 trafficking to the plasma membrane [5], in Golgi fragmentation prior to, or parallel with caspase activation [8] and in CD95 clustering in the plasma membrane (for a review, see [9]). Furthermore, ceramide can artificially alter membrane traffic and the lipid composition of diverse organelles [10]. On the other hand, CD95 engagement was reported to induce a rapid apoptotic cell volume decrease, which in part involves opening of ion channels in the plasma membrane and the release of organic osmolytes, such as taurine (for a review, see [9]). The role of apoptotic volume decrease for execution of apoptosis is under discussion. However, hyperosmotic hepatocyte shrinkage not only triggers volume regulatory responses, but also induces ligand-independent activation of the CD95 death receptor [3]. Thus the possibility must be considered that CD95 ligationinduced endocytosis is part of a volume-regulatory response, whose role in apoptosis induction is far from being clear. Surprisingly, collapse of the MMP and apoptosis induction in response to CD95L were caspase-inhibitor-sensitive, whereas CD95L-induced endocytosis was not. This is difficult to reconcile with the proposed key role of endocytosis in the propagation and amplification of CD95-activated signalling. In the study by Received 29 May 2008/3 June 2008; accepted 4 June 2008 Published on the Internet 15 July 2008, doi:10.1042/BJ20081094 c The Authors Journal compilation c 2008 Biochemical Society Matarrese et al. [7], monensin inhibited both CD95L-induced endocytosis and apoptosis, suggesting that endocytosis is important for apoptosis induction. However, monensin may also inhibit acidification of intracellular vacuoles and prevent their exocytosis, which is required for the recruitment of intracellularly stored CD95 to the plasma membrane in order to amplify early CD95 signalling [5]. Despite these uncertainties in defining the role of endocytosis in apoptosis induction in type II cells, these and previous observations by Matarrese et al. [6,7] open an interesting field of research on the interplay between death receptor engagement and intracellular membrane flow. Clearly, the consequences of CD95 receptor ligation are much more complex than previously thought, and it appears that multiple amplification loops become activated very early in response to CD95 ligation, which can transform this ‘snowball’ into the ‘avalanche’ of cell death. REFERENCES 1 Scaffidi, C., Fulda, S., Srinivasan, A., Friesen, C., Li, F., Tomaselli, K. J., Debatin, K. M., Krammer, P. H. and Peter, M. E. (1998) Two CD95 (APO-1/Fas) signalling pathways. EMBO J. 17, 1675–1687 2 Lee, K. H., Feig, C., Tchikov, V., Schickel, R., Hallas, C., Schütze, S., Peter, M. E. and Chan, A. C. (2006) The role of receptor internalization in CD95 signaling. EMBO J. 25, 1009–1023 3 Reinehr, R., Schliess, F. and Häussinger, D. (2003) Hyperosmolarity and CD95L trigger CD95/EGFR association and tyrosine phosphorylation of CD95 as prerequisites for CD95 membrane trafficking and DISC formation. FASEB J. 17, 731–733 4 Sodeman, T., Bronk, S. F., Roberts, P. J., Miyoshi, H. and Gores, G. J. 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