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Related Concept Videos

Caspases01:24

Caspases

Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside cells.
Necrosis01:16

Necrosis

Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become anucleated and die, but their...
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Apoptosis01:30

Apoptosis

Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size reduction of the tissue.
Overview of Cell Death01:30

Overview of Cell Death

Cell death is an essential process where the body gets rid of old or damaged cells. Cell proliferation and death need to be balanced, as an imbalance between the two may lead to cancer or autoimmune diseases.
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the 20th century...

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Related Experiment Video

Updated: May 28, 2026

Measuring Caspase Activity Using a Fluorometric Assay or Flow Cytometry
05:29

Measuring Caspase Activity Using a Fluorometric Assay or Flow Cytometry

Published on: March 24, 2023

Caspase 8 inhibits programmed necrosis by processing CYLD.

Marie Anne O'Donnell1, Eva Perez-Jimenez, Andrew Oberst

  • 1Immunology Institute, Mount Sinai School of Medicine, New York, New York 10029, USA. marie.a.odonnell@mssm.edu

Nature Cell Biology
|November 1, 2011
PubMed
Summary
This summary is machine-generated.

Caspase 8 prevents programmed necrosis by cleaving CYLD, a key substrate. This cleavage generates a survival signal, but a mutation preventing cleavage triggers necrotic cell death, highlighting CYLD

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Evaluation of Caspase Activation to Assess Innate Immune Cell Death
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Evaluation of Caspase Activation to Assess Innate Immune Cell Death

Published on: January 20, 2023

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Last Updated: May 28, 2026

Measuring Caspase Activity Using a Fluorometric Assay or Flow Cytometry
05:29

Measuring Caspase Activity Using a Fluorometric Assay or Flow Cytometry

Published on: March 24, 2023

Evaluation of Caspase Activation to Assess Innate Immune Cell Death
10:23

Evaluation of Caspase Activation to Assess Innate Immune Cell Death

Published on: January 20, 2023

Area of Science:

  • Cellular Biology
  • Molecular Mechanisms of Cell Death

Background:

  • Caspase 8 initiates apoptosis but primarily functions to suppress programmed necrosis (necroptosis) via RIPK1 and RIPK3.
  • Caspase 8's necroptosis-suppressing role requires catalytic activity, not apoptosis-related autocleavage.
  • The specific substrate targeted by caspase 8 to block necrosis has remained unidentified.

Purpose of the Study:

  • To identify the crucial substrate processed by caspase 8 that mediates the suppression of programmed necrosis.
  • To validate potential substrates based on their essentiality in necrosis, cleavage by caspase 8, and the effect of mutations on cell fate.

Main Methods:

  • Investigated the role of CYLD (deubiquitinase) as a potential substrate for caspase 8 in TNF-induced cell death.
  • Assessed CYLD cleavage by caspase 8 in conditions where caspase 8 suppresses necrosis.
  • Utilized site-directed mutagenesis to create a non-cleavable CYLD mutant (Asp 215) and evaluated its impact on TNF-induced cell death.

Main Results:

  • Identified CYLD as a direct substrate of caspase 8, crucial for generating a pro-survival signal following TNF stimulation.
  • Demonstrated that caspase 8-mediated cleavage and degradation of CYLD is essential for preventing necrotic cell death.
  • Showed that a CYLD mutant resistant to caspase 8 cleavage at Asp 215 triggers necrotic cell death instead of survival upon TNF stimulation.

Conclusions:

  • CYLD is the key substrate processed by caspase 8 to block programmed necrosis, fulfilling all criteria for a critical mediator.
  • Caspase 8-dependent cleavage of CYLD is essential for transmitting a pro-survival signal and preventing TNF-induced necroptosis.
  • Dysregulation of CYLD processing by caspase 8 can shift the cell fate from survival to necrotic death.