TNF Family Receptors

See also signal transduction

The 29 receptors identified so far in humans that belong to the TNF receptor (TNFR) superfamily are characterized by the presence of a cytstein-rich domain (CRD) in the extracellular portion. Four cellular receptors induce apoptosis after ligation; they are the Fas receptor, p55 tumor necrosis factor (TNF) receptor, and TRAIL/APO 2-L (TNF-related apoptosis-inducing ligand) receptors 1 and 2. Fas Ligand (Fasl), TNF, and TRAIL/APO2-L, respectively, bind these receptors to initiate apoptosis.

TNF receptors interact with a family of molecules called TRAFs (TNF receptor-associated factors) that act as adaptors for downstream signaling events. For example, TRAF2 activates NF-κB and also c-Jun NH2-terminal kinase (JNK).

TNFR1 and Fas are unique among the TNF receptor family in having cytoplasmic death domains. Most other family members function in costimulation of immune responses rather than induction of apoptosis. Some of them, such as CD40, even enhance cell survival and protect against apoptosis.

death domain containing receptors (DD) in the cytoplasmic tail are contained in the first major TNF receptor group. Receptors included in this group include TNF-R1, DR3, TRAIL-R1, TRAIL-R2, and DR6. Activation of these death domain containing receptors by their corresponding ligands can lead to recruitment of intracellular death domain containg adaptors such as Fas associated death domain (FADD) and TNFR associated DD (TRADD). These molecules, in turn cause activation of the capsase cascade and induction of apoptosis.

The death domain containing receptors are a subset of the Type I transmembrane TNF-receptor superfamily proteins defined by the presence of a death domain in their cytoplasmic domains. This protein associated domain is found in TNF-R1 and Fas as well as several others. While these receptors share some mechanisms of signal transduction, they are not identical. Fas, TRAIL-R1 and TRAIL-R2 interact with FADD while TNF-R1 and DR3 interact with the adaptor TRADD.

  • TRAIL/APO-2L Receptors: TRAIL receptors can be divided into two groups, death inducing receptors (TRAIL-R1 and -R2) and death-inhibitory receptors (TRAIL-R3 and -R4). This suggest a complex regulation of cellular susceptibility to TRAIL-mediated apoptosis at the level of multiple receptor expression.

(1) TRAIL-R1:

(2) TRAIL-R2:

(3) TRAIL-R3 competes with the death-inducing TRAIL-Rs for TRAIL binding and may work as a decoy receptor. It is thought that TRAIL-R3 might be responsbile for the cellular resistance of normal cells to TRAIL-mediated cytooxicity since its mRNA was preferentially found in normal but not transformed cells.

(4) TRAIL-R4 has the cytoplasmic domain containg a truncated death domain that cannot transmit a death signal but can activate NF-kB, which may protect the cells from TRAIL-mediated apoptosis.

  • Fas (APO-1, CD95): Fas is a transmembrane protein belonging to the TNF receptor family and transduces the death signaling upon stimulation by Fas ligand, providing an important mechanism for cell death mediated by activated cytotoxic T lymphocytes and NK cells. Upon stimulation, CD95 recruits a "death-inducing signaling complex" (DISC) to the membrane. The principal signaling components in the DISC are the adapter protein FADD/MORT1 and procaspase-8. During DISC formation, procaspase-8 is activated.

In some cells activate caspase-8 is sufficient to activate caspase-3 directily ("tyle I cells"). In other cells, however, CD95-mediated caspase-8 activation is not enough to activate caspase-3 and a mitchondrial amplification is necessary: the cleavage of the proapoptotic Bcl-2 family member Bid by caspase-8 cause the release of mitochondrial cytocrome c, thus feeding into the central apoptosis pathway (tyep II cells)

Fasl transcripts are predominantly restricted to stimulated T cells and sites of immune privilege (e.g., corneal epithelium). it is important to note that there is significant variation between cell lines regarding the level of apoptosis that can be induced via Fas receptor.

  • TNFR1 : In contrast to Fas, TNFR1 only signals for cell death in certain circumstances (e.g., when protein synthesis is blocked). In most scenarios, TNFR1 instead induces the transcription and activation of inflammatory genes. TNF binds to TNFR1. The TNFR1 signaling complex leads to activation of at least three distinct effector functions, induction of apoptosis, NF-kB activation and JNK activation.

When TNF binds to TNFR1, the trimerized receptor recruits TNFR-associated protein with death domain (TRADD) via interactions between death domains. TRADD then binds Fas-associated protein with death domain (FADD) which in turn binds to and promotes the activation of caspase-8, one of the initiator apoptotic proteases.

Alternatively, TRADD can recruit TRAF2, TRAF1 and receptor-interacting protein (RIP) to activate the NF-kB and JNK pathways, which protect cells from apoptosis and initiate inflammatory responses.  First, TNFR-1 activates procaspase-2 through the binding of TRADD to the adaptor molecules receptor-interacting protein (RIP) and RIP-associated ICE-homologous protein with death domain RAIDD. Second, through the binding of TRADD to the downstream transducer TNFR-associated factor-2 TRAF2 and the protein kinase NF-kB-inducing kinase (NIK), TNFR-1 also activates the transcription factor NF-kB, which activates transcription of polypeptides such as cIAP1 and cIAP2 that antagonize the FADD-mediated death signals. As a consequence of this latter pathway, many cells fail to undergo TNF-α-induced cell death unless inhibitors of the NF-kB pathway (e.g., protein synthesis inhibitors, RNA transcription inhibitors, or the IkB superressor) are included.

The JNK pathway like NF-kB activation is also mediated via TRAF2 and RIP recruitment.

Thus, in a dichtomy of activation, TNF-R1 assembles a signaling complex that activates both the capase-8 apoptotic and the NF-kB and JNK anti-apoptotic pathways. This balance is regulated at numerous levels including strenght of signal, regualtion of receptor expression and anti-apoptotic gene induction.

  • TRAF-interacting motif (TIMs) containing receptors. Receptors included in this group include TNF-R2, CD40, CD30, CD27, LTBR, Ox40, 4-1BB, BAFF-R, BCMA, TACI, RANK, p75NGFR, HVEM, TNFRSF18, TROY, EDAR, XEDAR, RELT and Fn14. Activation of TIM containing TNF receptors leads to recruitment of TRAF family members, and activation of multiple signal transduction pathways such as nuclear factor kB (NF-kB), Jun N-terminal Kinase (NJK), p38, extra-cellular signal-related kinase (ERK) and phosphoinositide 3-kinase (PI3K)
  • non-intracellular signal domain containing receptors cannot provide intracellular sigaling. But they can effectively compete with the other two signaling groups of receptors for their corresponding ligands.. Thus they are sometimes referred to as "decoy receptors" and function by impeding the activation of signal transduction pathways by other TNF receptors.
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