The CD95/APO-1/Fas signaling pathway
Apoptosis is induced by the
triggering of the tumor necrosis factor (TNF) superfamily of death receptors. These
receptors are characterized by the presence of a protein-protein interaction
domain (called death domain, DD) in their cytoplasmic tail. These are tumor necrosis
factor receptor-1 (TNF-R1, also known as DR1, CD120a, p55 or p60), CD95 (also
known as DR2, APO-1 or Fas), DR3 (also known as APO-3, LARD, TRAMP or WSL1),
TNF-related apoptosis-inducing ligand receptor 1 (TRAIL-R1, also known as DR4
or APO-2), TRAIL-R2 (also known as DR5, KILLER, or TRICK2), DR6, ectodysplasin
A receptor (EDAR) and nerve growth factor receptor (NGFR) [1]. Binding of their respective ligand triggers
the recruitment of a set of molecules transducing apoptotic and/or survival
signals.
Amongst the death receptors, CD95
is one of the best characterized members. CD95 is expressed in most tissues,
and has been shown to induce apoptosis in lymphocytes, brain, pancreas and
liver. Triggering of CD95 by its ligand (CD95-L) leads to the oligomerization of
CD95 and the assembly of a typical multi-protein complex called death inducing signaling
complex (DISC) (Fig. 1) [2]. It has also been reported that CD95 self-associates as
trimers before CD95-L binding via an extracellular domain called PLAD
(pre-ligand association domain).
Formation of pre-associated receptors is essential for downstream CD95
signaling [3, 4]. The DISC formation allows the recruitment and activation of initiator
caspases (caspases -2, -8 or -10), mediated by the adaptor molecule FADD. FADD contains
two protein-protein interaction domains (DD and DED) and links the receptor to initiator
caspases through homotypic interactions [5-7]. The recruitment of
procaspase-8 to the DISC leads to its activation through dimerization of
monomeric zymogens and autocatalytic cleavage [8-10]. The caspase-8 prodomain remains at the DISC
whereas caspase-8 active heterotetramer is released into the cytosol to
propagate the apoptotic signal through activation of executioner caspases,
namely caspases-3, -6 and -7. Beside caspase-8, caspases-2 and -10 are also found at the
DISC but their role in the CD95-induced caspases cascade activation is still a
matter of debate in the literature [7, 11-15].
Two
pathways of CD95 apoptosis signaling, depending on the amount of active
caspase-8 generated at the DISC, have been described [16]. In type I cells, a large quantity of active
caspase-8 can directly cleave procaspase-3, starting a caspases cascade that
bypasses the mitochondria (Fig. 1). By contrast, type II cells show a reduced
DISC formation and depend on an amplification loop via the mitochondria. Apoptosis in these cells is dependent, at
least in part, on the cleavage of the BH3-only pro-apoptotic Bcl-2 homologue
Bid. Truncated Bid (tBid) then migrates to the mitochondria where it induces the
release of cytochrome c into the cytosol [17]. This is followed by the formation of the apoptosome.
This complex, composed of cytochrome c, APAF-1 and dATP permits the recruitment
and activation of the typical initiator caspase of the mitochondrial apoptotic
pathway, namely caspase-9 [18].
One
major regulator of CD95-mediated apoptosis at the DISC level is cellular FLIP
(c-FLIP). It contains tandem DEDs and a caspase-like domain. The inhibition of
apoptosis by c-FLIP was shown to be mediated by its recruitment and cleavage in
the DISC instead of procaspase-8, preventing the cleavage and activation of the
functional enzyme and the subsequent transduction of apoptotic signal (Fig. 1) [19].
CD95-induced
apoptosis plays an important role in the homeostasis of many cell types in the
human body. It is involved in the down-regulation of the immune response via
the so-called Activation-Induced Cell Death
(AICD), characterized by the death of preactivated lymphocytes upon the
restimulation of their T cell receptors [20, 21]. In mice, lpr, lprcg
and gld mutations are associated with defects in the CD95 pathway,
accounting for autoimmunity, abnormal accumulation of T and B cells and
lymphadenopathy [22]. The lpr mutation is associated with
the insertion of a retrotransposon into intron 2 of the CD95 gene, leading to
an important decrease in CD95 surface expression [23]. Lprcg is a single point
mutation within the death domain of CD95, thereby abrogating downstream signaling
[24]. Finally, the gld mutation causes the
expression of a defective CD95-L [25]. In human, mutation in CD95 or CD95-L
genes (or related molecules) can lead to an lpr-like pathology known as
autoimmune lymphoproliferative syndrome (ALPS) [22]. CD95 is also expressed by various epithelial
cells. CD95-dependent apoptosis is implicated in the pathogenesis of liver
injury induced by many noxes [26], and defective expression of CD95 is often
described in solid tumors, thereby accounting for apoptosis resistance [27]. Finally, it was recently shown that CD95
mediates non-apoptotic functions [28].
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