Death-inducing signaling complex

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The death-inducing signaling complex or DISC is a multi-

FasL) binding. The DISC is composed of the death receptor, FADD, and caspase 8
. It transduces a downstream signal cascade resulting in apoptosis.

Description

The

dimerization
process with other procaspase-8 molecules, known as an induced proximity model.

Forming complex

The CAP proteins associate only with the

FLICE
must be activated. In its inactive state, FLICE's two death domains are thought to bind together and prevent its activation. Once APO-1 aggregates within the cytosol, it recruits FADD, CAP3, and FLICE to the receptor, where FLICE is modified into several active subunits, which have the ability to cleave a variety of substrates. This proteolytic activity then results in a cascade of caspase activation, and ultimately cell death. This apoptotic activity is critical for tissue homeostasis and immune function.

Inhibiting factors

APO-1-mediated apoptosis can be inhibited by a variety of factors, including the viral caspase inhibitors

CrmA and p35
, as well as viral FLICE-inhibitory proteins known as v-FLIPs. When in the presence of APO-1, v-FLIPs preferentially bind and prevent procaspase-8 from being recruited; as such, apoptosis is stalled. Humans have a homolog for v-FLIP known as c-FLIP, which occurs in two endogenous forms (c-FLIPL (long) and c-FLIPS (short)). These are similar in structure to procaspase-8, but lack the amino acids necessary for caspase-8 catalytic activity. It is thought that c-FLIP may be involved in modulating the immune system, as c-FLIPS is upregulated upon stimulation of the T cell receptor. Furthermore, as high expression of FLIP is known to promote tumor growth, these inhibitor molecules play a role in cancer proliferation.

The DISC has been implicated as a possible drug development target for various cancers, including leukemia, glioma, and colon cancer. In glioma cells, the effects of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) have been shown to induce DISC-mediated apoptosis. Specifically, TRAIL works by activating two death receptors, DR4 and DR5; these bind to FADD, which then interacts with caspase-8 to assemble the DISC. Tumor cells show varying sensitivity to TRAIL modulated apoptosis, depending on the presence of the antiapoptotic FLIP proteins.[6] Additionally, studies in leukemia have indicated that the histone deacetylase inhibitor LAQ824 increases apoptosis by decreasing the expression levels of the c-FLIPs.[7] As such, these inhibitors are promising targets for anti-cancer therapy.

References

  1. PMID 8521815
    .
  2. PMID 8521815
    .
  3. PMID 11279218
    .
  4. PMID 9184224
    .
  5. PMID 8681377
    .
  6. PMID 11976344
    .
  7. PMID 15059915
    .

External links
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