Death Receptors

In contrast to the effect of growth factors, a number of cytokines that bind to cell surface receptors that are members of the TNF receptor superfamily can induce apoptosis. These death receptors possess similar cysteine-rich extracellular domains but lack substantial homology in their cytoplasmic regions except in the "death domain," which spans approximately 80 amino acids and which is required for transduction of the death signal. Members of this family include TRAMP (also known as DR3, Apo3, WSL-1, or LARD), the TRAIL receptors 1 and 2, avian CAR1, DR4, the Fas receptor (also known as CD95 or Apo1), and the TNF receptors (TNFR1 and TNFR2). TRAMP is expressed at highest levels in lymphocytes and thymocytes and is predicted to function in lymphocyte maturation. The only function currently attributed to TRAIL receptors is the induction of apoptosis in tumor cells. Two proteins related to the TRAIL receptors are decoys (DcR1 and DcR2) that are primarily expressed in normal cells, do not have a functional death domain, and confer resistance to TRAIL action. CAR1 and DR4 are poorly characterized. The most extensively studied members of this group are the Fas receptor (Fas R) and the TNF-1 receptor (TNFR1). The regulation of apoptosis by these receptors is a useful model for predicting the behavior of other members of this superfamily.

The Fas receptor is the only member of this family that appears to act primarily in the apoptotic pathway. This receptor is expressed in diverse tissues, but is chiefly involved in the modulation of the immune response. Binding of Fas ligand (Fas L) to this receptor mediates cell killing by cytotoxic T and NK cells, and induces apoptosis in activated T cells. Expression of Fas L also confers immune privilege on the eye (and probably other tissues) and on some tumors by inducing apoptosis in infiltrating cytotoxic T cells. The importance of Fas signaling in the immune system is emphasized by the phenotypes of several strains of mice in which the Fas signal transduction pathway has been interrupted by the alteration of either the Fas receptor or Fas ligand. The negative selection of T cells occurs normally in both strains of animal but they all develop autoimmune disorders and accumulate immature CD4-CD8- T cells. Production of auto-antibodies in these mice also suggests that the Fas receptor may be involved in appropriate B-cell response.

Proteins that contain death domains can associate with one another by interaction of these regions. Binding of Fas ligand to the Fas receptor causes receptor oligomerization via the death domains and subsequent recruitment of the adapter protein FADD/Mort 1 (which also contains a death domain) to the clustered receptor. This adapter protein then recruits caspase-8 to form the death-inducing signaling complex (DISC). This initiator caspase then undergoes activation by autodigestion and acts on other caspases in an amplifying cascade that culminates in the final stages of apoptosis. In some instances, the serine/threonine kinase RIP associates with FADD (instead of pro-caspase-8) and induces apoptosis by an unknown mechanism. Fas receptor can alternatively associate with Daxx (instead of FADD), which induces apoptosis by activation of the JNK pathway. The interaction of the Fas receptor with these proteins is illustrated in Fig. 2. Other proteins that can interact with the Fas receptor include sentrin, FAF1, which is able to potentiate apoptosis in L cells, and FAP-1, a protein tyrosine phosphatase that inhibits Fasmediated apoptosis of T cells.

Ceramide Signaling

Fig. 2. Fas-mediated death signalling. Binding of Fas ligand to the Fas receptor causes receptor oligomerization followed by recruitment of adapter proteins to the cytoplasmic domain. The best characterized of these adapter proteins are FADD and DAXX. Binding of FADD causes recruitment of procaspase-8 (which is then activated) to form the death inducing signaling complex. In some cases, proteins other than procaspase-8 (such as RIP) may associate with FADD and regulate cell death via poorly characterized pathways. Association of DAXX with the Fas receptor instead of FADD causes activation of Jun Kinase, followed by altered transcription of genes involved in regulation of apoptosis.

Fig. 2. Fas-mediated death signalling. Binding of Fas ligand to the Fas receptor causes receptor oligomerization followed by recruitment of adapter proteins to the cytoplasmic domain. The best characterized of these adapter proteins are FADD and DAXX. Binding of FADD causes recruitment of procaspase-8 (which is then activated) to form the death inducing signaling complex. In some cases, proteins other than procaspase-8 (such as RIP) may associate with FADD and regulate cell death via poorly characterized pathways. Association of DAXX with the Fas receptor instead of FADD causes activation of Jun Kinase, followed by altered transcription of genes involved in regulation of apoptosis.

Engagement of the TNFR1 can cause proliferation, differentiation, or apoptosis (the latter generally occurs only in the presence of protein synthesis inhibitors). These pleiotropic effects are determined by which proteins are recruited to the adapter protein TRADD, which binds to TNFR1 after ligand binding.

One protein that may associate with TRADD is FADD. As is the case when FADD associates with the Fas receptor, procaspase-8 is then recruited to FADD and activated, and the downstream events of apoptosis commence. Binding of TRAF2 to TRADD causes activation of the transcription factor NF-kB, which is associated with suppression of apoptosis in most cell types. Another protein that may associate with TRADD is RIP, which may also mediate NF-kB activation. In other instances, RIP recruits RAIDD/ CRADD, leading to activation of caspase-2 and therefore apoptosis. Additional proteins that can associate with the TNFR1 include 55.11, sentrin, TRAP-1,

MADD, and FAN. The functions of the first three are unknown; however, association with MADD leads to activation of ERK and SAPK/JNK, and association with FAN is able to activate neutral sphingomyelinase (NSMase) and thereby induce generation of ceramide, which has been implicated in induction of apoptosis.

The role of ceramide in apoptosis has been the subject of intense investigation as well as some controversy. Ceramide is generated by the activity of ceramide synthetase or by the hydrolysis of sphingo-myelin by neutral or acidic sphingomyelinases. Cera-mide may initiate differentiation, proliferation, or apoptosis depending on the cell type. Synthetic analogs of this sphingolipid can induce apoptosis in many cells; however, ceramide signaling is not universally required for induction of apoptosis, and the importance of this messenger in signal transduction via physiological inducers of programmed cell death is still a matter of debate. Although the Fas receptor and TNFR1 can both activate acidic and neutral sphingomyelinases, studies using various inhibitors of ceramide signaling suggest that they play no role in apoptosis induced by these receptors. Supporting this conclusion are experiments performed with cells from patients with Neimann-Pick disease, which lack functional acidic sphingomyelinase. These cells are resistant to apoptosis induced by ionizing radiation, but not to apoptosis induced by Fas ligand or TNF-a. Thus, it appears that ceramide may be important in some apoptotic signal transduction pathways but not others, or perhaps only in certain cell types or in combination with other modulatory signals.

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment