Death-inducing signaling complex

Death-inducing signaling complex (DISC) is a multi-protein complex formed in the cells in response to extrinsic signals that lead to apoptosis, or programmed cell death. The formation of DISC is a critical step in the extrinsic pathway of apoptosis, which is one of the two main pathways through which cells can initiate apoptosis, the other being the intrinsic or mitochondrial pathway.

Formation and Components

The DISC is formed when a death receptor on the cell surface, such as Fas (also known as CD95) or tumor necrosis factor receptor 1 (TNFR1), binds to its corresponding ligand. This binding leads to the recruitment of several adaptor proteins and initiator caspases to the intracellular part of the receptor, creating the DISC. The most critical components of the DISC include:

• Fas-associated death domain (FADD) - An adaptor protein that is essential for the recruitment of caspases to the death receptors.
• Procaspase-8 (or Procaspase-10 in some cells) - An inactive form of caspase-8, which is a cysteine-aspartic acid protease that plays a crucial role in apoptosis. Within the DISC, procaspase-8 is cleaved to its active form, caspase-8, initiating the caspase cascade that leads to cell death.

Function

The primary function of the DISC is to transduce the death signal from the cell surface to the intracellular signaling pathways that execute apoptosis. Upon formation, the DISC activates caspase-8, which in turn can directly cleave and activate downstream effector caspases, such as caspase-3, -6, and -7. These effector caspases then go on to cleave a variety of cellular substrates, leading to the morphological and biochemical changes associated with apoptosis.

In addition to directly activating effector caspases, caspase-8 can also cleave a protein called Bid, a member of the Bcl-2 family. The truncated form of Bid (tBid) can translocate to the mitochondria and promote the release of cytochrome c, linking the extrinsic pathway of apoptosis to the intrinsic pathway and amplifying the apoptotic signal.

Regulation

The activity of the DISC and the initiation of apoptosis are tightly regulated by various cellular factors. For example, cellular FLICE-inhibitory protein (c-FLIP) can be recruited to the DISC, where it inhibits the activation of procaspase-8, thereby preventing apoptosis. Other regulatory mechanisms include the expression levels of death receptors and their ligands, post-translational modifications of DISC components, and the balance between pro-apoptotic and anti-apoptotic Bcl-2 family proteins.

Clinical Significance

Dysregulation of apoptosis, including the signaling through the DISC, is implicated in a wide range of diseases. In cancer, for example, cells often acquire mutations that disrupt the apoptotic pathways, allowing them to survive and proliferate uncontrollably. Conversely, excessive apoptosis can contribute to degenerative diseases and immunodeficiency. Understanding the mechanisms of DISC formation and function is therefore crucial for the development of therapeutic strategies targeting apoptosis in various diseases.

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