Death-inducing signaling complex: Difference between revisions

Latest revision as of 16:32, 16 February 2025

Death-inducing Signaling Complex[edit]

The death-inducing signaling complex (DISC) is a multi-protein complex that forms upon the activation of death receptors on the cell surface. This complex plays a crucial role in the process of apoptosis, which is a form of programmed cell death essential for maintaining cellular homeostasis and development in multicellular organisms.

Structure[edit]

The DISC is primarily composed of the following components:

Fas receptor (CD95): A member of the tumor necrosis factor receptor (TNFR) superfamily, which is activated by binding to its ligand, Fas ligand (FasL).
FADD (Fas-associated protein with death domain): An adaptor protein that connects the Fas receptor to downstream signaling molecules.
Caspase-8: An initiator caspase that is recruited to the DISC and activated through dimerization and cleavage.

Formation[edit]

The formation of the DISC is initiated when the Fas receptor binds to Fas ligand. This binding induces trimerization of the Fas receptor, which then recruits the adaptor protein FADD through interactions between their respective death domains. FADD, in turn, recruits procaspase-8 via its death effector domain, leading to the formation of the DISC.

Function[edit]

The primary function of the DISC is to initiate the extrinsic pathway of apoptosis. Upon formation, procaspase-8 is activated through dimerization and subsequent autocatalytic cleavage. Active caspase-8 then cleaves and activates downstream effector caspases, such as caspase-3, which execute the apoptotic program by cleaving various cellular substrates.

Regulation[edit]

The activity of the DISC is tightly regulated by several mechanisms to ensure appropriate cellular responses. Regulatory proteins such as c-FLIP (cellular FLICE-inhibitory protein) can inhibit the activation of caspase-8 by competing with it for binding to FADD, thus modulating the sensitivity of cells to Fas-mediated apoptosis.

Clinical Significance[edit]

Dysregulation of DISC components can lead to various diseases. For example, impaired Fas signaling can result in autoimmune disorders due to the failure to eliminate autoreactive lymphocytes. Conversely, excessive activation of the DISC can contribute to tissue damage in conditions such as liver hepatitis and neurodegenerative diseases.

Related Pages[edit]

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-'''Death-inducing signaling complex''' (DISC) is a multi-protein complex formed in the [[cell]]s 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.
+== Death-inducing Signaling Complex ==
-==Formation and Components==
+[[File:Fas_signaling.jpg|thumb|right|Diagram of Fas signaling pathway]]
-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.
+The '''death-inducing signaling complex''' (DISC) is a multi-protein complex that forms upon the activation of [[death receptors]] on the cell surface. This complex plays a crucial role in the process of [[apoptosis]], which is a form of programmed cell death essential for maintaining cellular homeostasis and development in multicellular organisms.
-* '''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==
+=== Structure ===
-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.
+The DISC is primarily composed of the following components:
-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.
+* '''[[Fas receptor]] (CD95):''' A member of the [[tumor necrosis factor receptor]] (TNFR) superfamily, which is activated by binding to its ligand, [[Fas ligand]] (FasL).
+* '''[[FADD]] (Fas-associated protein with death domain):''' An adaptor protein that connects the Fas receptor to downstream signaling molecules.
+* '''[[Caspase-8]]:''' An initiator caspase that is recruited to the DISC and activated through dimerization and cleavage.
-==Regulation==
+=== Formation ===
-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.
+The formation of the DISC is initiated when the Fas receptor binds to Fas ligand. This binding induces trimerization of the Fas receptor, which then recruits the adaptor protein FADD through interactions between their respective death domains. FADD, in turn, recruits procaspase-8 via its death effector domain, leading to the formation of the DISC.
-==Clinical Significance==
+=== Function ===
-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.
+The primary function of the DISC is to initiate the extrinsic pathway of apoptosis. Upon formation, procaspase-8 is activated through dimerization and subsequent autocatalytic cleavage. Active caspase-8 then cleaves and activates downstream effector caspases, such as [[caspase-3]], which execute the apoptotic program by cleaving various cellular substrates.
+=== Regulation ===
+The activity of the DISC is tightly regulated by several mechanisms to ensure appropriate cellular responses. Regulatory proteins such as [[c-FLIP]] (cellular FLICE-inhibitory protein) can inhibit the activation of caspase-8 by competing with it for binding to FADD, thus modulating the sensitivity of cells to Fas-mediated apoptosis.
+=== Clinical Significance ===
+Dysregulation of DISC components can lead to various diseases. For example, impaired Fas signaling can result in autoimmune disorders due to the failure to eliminate autoreactive lymphocytes. Conversely, excessive activation of the DISC can contribute to tissue damage in conditions such as [[liver]] [[hepatitis]] and [[neurodegenerative diseases]].
+== Related Pages ==
+* [[Apoptosis]]
+* [[Caspase]]
+* [[Death receptor]]
+* [[Fas ligand]]
+* [[FADD]]
+{{Apoptosis}}
-[[Category:Cell biology]]
 [[Category:Apoptosis]]
-{{biology-stub}}
+[[Category:Cell signaling]]