Internalization of death receptors

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

Internalization of cell-surface receptors is an initial step in the endocytosis pathway, leading either to recycling of receptors back to the surface or ultimately targeting receptors for lysosomal degradation (87). For a long time, internalization and endocytotic trafficking were thought to terminate death-receptor signaling. However, receptor internalization can be essential to fully perpetuate the death signal (88–89).

During Fas-induced apoptosis, Fas receptors become clustered, translocate to cytoskeleton-linked lipid rafts and form higher-order aggregates by interacting with actin filaments (60,90). This process is regulated by Fas palmitoylation and ezrin-mediated cytoskeleton association (60–61,91). At this early stage, DISC formation in lipid rafts is limited and can be detected microscopically as signaling protein oligomerization structures (SPOTS) (92). Subsequent formation of large lipid-raft platforms induces Fas internalization in a clathrin-dependent manner (93–94). Fas is then delivered to early endosomes, where DISC complexes increase in abundance and caspase-8 activity increases dramatically (95). While internalization of Fas is required for apoptosis, non-cytotoxic Fas signaling such as NFB and mitogen-activated protein kinase (MAPK) pathways do not require internalization (95).

Receptor internalization is also shown to be critical for TNF-R1induced cell death (96). Upon ligand binding, TNFR1 recruits TRADD, TRAF2, RIP1, and cIAP1/2 to form complex I to activate the NFB signaling pathway. Shortly after complex I formation, TNF-R1 is internalized through clathrin-mediated endocytosis and NFB signaling is terminated (97). Subsequent events regarding caspase-8 activation are controversial. Early studies suggested that RIP1 is dissociated from TNF-R1 during endocytosis, allowing the DD of RIP1 to bind FADD and recruit caspase-8/-10 to form the cytosolic complex II (also referred to as complex IIA; 98) to trigger apoptosis (99). The composition of this cytosolic complex was later questioned by using magnetic sorting to isolate TNF–TNF-R1 complexes from endosomal compartments (100). These findings suggest that FADD and caspase-8/-10 are recruited to form a death-inducing cytosolic TNF-R1-associated DISC (also referred as receptosome; Figure 30.8).

Both TRAIL-R1 (DR4) and TRAIL-R2 (DR5) receptors were reported to be internalized shortly after ligand binding through a clathrin-dependent or caveolin-dependent pathway (101–102). However, unlike Fas and TNF-R1-induced signaling, internalization is not required for TRAIL-induced apoptosis in type I cells (103). It is important to note that the molecular details of death-receptor signaling pathways are active areas of research and are not fully understood.


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