Death-receptor-induced non-apoptotic pathways

Molecular oncology. Causes of cancer and targets for treatment. Cambridge University Press (2014)

Death receptors are well known to induce cell death, but they also promote cell survival, proliferation, differentiation, and inflammatory responses, mainly through activating NF-kB and MAPK pathways (83). These multiple functions of death receptors reside in their ability to form distinct signaling complexes (Figure 30.8). Bifurcation of the signaling pathways downstream of death receptors is regulated both temporally and spatially (83). For example, upon TNF binding, two signaling complexes are formed sequentially (99). The initial complex, complex I, consisting of TNF-R1, TRADD, TRAF2, RIP1/RIPK1, and cIAP1/2 is formed within minutes after ligand binding and activates the NF-kB signaling pathway to prevent cell death. Minutes later, TNF-R1 can be internalized to form the cytosolic caspase-8-activating complex II (containing RIP1, FADD, and caspase-8) or receptosome (containing TRADD, TRAF2, RIP1, FADD, and caspase-8; Figure 30.8; 104). Unlike the TNF-R1-induced DISC, which needs to be internalized to fully activate apoptosis, complex I does not require internalization and is sufficient to activate NFB at the cell surface (105–106).

Molecular Oncology. Causes of Cancer and Targets for Treatment-CUP (2014) F30.8

Figure 30.8. Cross-talk between extrinsic and intrinsic pathways. Active caspase-8 cleaves BID by generating pro-apoptotic truncated BID. tBID causes mitochondrial outer membrane permeabilization (MOMP) by activating pro-apoptotic BAX and/or by inhibiting anti-apoptotic Bcl-2 family members. BAX-induced pore formation in the outer mitochondrial membrane releases cytochrome c to trigger Apaf1 apoptosomemediated activation of initiator caspase-9, which in turn activates, cleaves and activates downstream executioner caspases.

Another important control point to signal cell death vs. survival is the kinase RIP1 (107). RIP1 is a DD-containing serine/threonine kinase that binds to death receptors and DD-containing adaptor proteins (108–109). Post-translational modification of RIP1 is a pivotal determinant of death vs. survival (110). Polyubiquitination of RIP1 mediated by the E3 activity of apoptosis inhibitors cIAP1, A20, TRAF2, TAK1, or LUBAC (linear ubiquitin chain assembly complex) is required for NF-kB and MAPK activations (111–115). Conversely, when ubiquitination is inhibited, for example by small-molecule Smac mimetics that induce cIAP degradation, the ubiquitin chain is removed by a deubiquitinase such as cylindromatosis (CYLD), and RIP1 switches from a pro-survival scaffold protein to a potent apoptosis inducer by forming complex II (IIA, Figure 30.8; 109, 116–117). Ubiquitination of RIP1 is suggested to stave off cell death long enough to allow the transcription activity of NFB to induce de novo expression of anti-death factors such as cFLIP. cIAP1 is readily cleaved by caspase-8 in vitro, which potently activates the E3 ubiquitin ligase activity of cIAP1, but the relevant in vivo manifestations of this event are not yet known (118). Delineation of the target substrates of RIP1–3 kinases and of the caspases that regulate this pathway will also be important to understand and treat human disease.

Recent studies reveal that RIP1, together with RIP kinase 3 (RIPK3/RIP3) play an important role in regulating TNF-induced necroptosis, a form of programmed necrosis (119–120). Necroptosis is the default alternative death pathway that occurs when the apoptotic pathway is inhibited, for example with caspase inhibitors (121–122). Necroptosis is mediated by complex IIB, containing RIP1 and RIP3 (98,107). When RIP1 is inhibited by the small-molecular inhibitor necrostatin-1 (Nec-1), necroptosis is inhibited, indicating that RIP1 plays an essential role in promoting this alternative death pathway (122). Unlike its role in NF-kB activation, RIP1-induced necrosis requires RIP1 kinase activity. When the RIP1 deubiquitinase CYLD is depleted by siRNA knockdown, necroptosis as well as apoptosis is blocked, suggesting that deubiquitinated RIP1 promotes necroptosis (119). RIP1 was recently reported to form the core of the “ripoptosome” complex that can be activated by genotoxic stimuli in the absence of death-receptor signaling. Regulated by cFLIP and cIAPs, this complex determines if cells die by RIP3-dependent necrosis or caspase-8-dependent apoptosis (123–124). The delineation of factors involved in genedependent necrosis is a major advancement, as the prospects of developing therapeutic agents that inhibit necrosis was not previously thought possible.


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