Related Experiment Video

Updated: Jan 3, 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

5.3K

Activity of caspase-8 determines plasticity between cell death pathways

Kim Newton1, Katherine E Wickliffe2, Allie Maltzman2

  • 1Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA. knewton@gene.com.

Nature
|November 15, 2019
PubMed

Insights

Inactive caspase-8 (CASP8) triggers lethal inflammation by activating caspase-1 and caspase-11 pathways, even when necroptosis is blocked. This reveals unexpected plasticity in cell death pathways.

Area of Science:

  • Cellular Biology
  • Immunology
  • Molecular Biology

Background:

  • Caspase-8 has dual roles, mediating apoptosis and suppressing necroptosis.
  • Mice lacking functional caspase-8 exhibit embryonic lethality, suggesting a pro-death scaffolding function.

Purpose of the Study:

  • To investigate the pro-death scaffolding function of inactive caspase-8.
  • To elucidate the molecular mechanisms underlying the lethality observed in mice with inhibited caspase-8 and MLKL.

Main Methods:

  • Utilized genetically modified mouse models (Casp8(C362A), Mlkl-/-, Casp1-/-, Asc-/-, Casp11-/-).
  • Analyzed caspase-1-dependent cleavage of GSDMD and downstream caspases.
  • Examined ASC speck formation and caspase-11 upregulation in intestinal tissues.

Main Results:

  • Inactive caspase-8 (CASP8(C362A)) induced ASC speck formation and caspase-1-dependent cleavage of GSDMD, caspase-3, and caspase-7 in MLKL-deficient mice.
  • Caspase-1 and ASC were critical for the perinatal lethal phenotype.
  • Upregulation of caspase-11 also contributed to lethality.
  • A necroptosis-independent function of RIPK3 also contributed to lethality.

Conclusions:

  • Inactive caspase-8 possesses a pro-death scaffolding function that activates inflammatory caspases (caspase-1 and caspase-11).
  • This pathway involves ASC speck formation and GSDMD cleavage, leading to perinatal lethality.
  • The study reveals significant plasticity in cell death pathways, with implications for understanding inflammatory diseases.

More Related Videos

Evaluation of Caspase Activation to Assess Innate Immune Cell Death10:23

Evaluation of Caspase Activation to Assess Innate Immune Cell Death

Published on: January 20, 2023

3.7K
In Vivo Biosensor Tracks Non-apoptotic Caspase Activity in Drosophila13:21

In Vivo Biosensor Tracks Non-apoptotic Caspase Activity in Drosophila

Published on: November 27, 2016

9.5K

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...
13.6K
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...
7.9K
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...
8.1K
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...
9.2K
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...
13.8K
Autophagic Cell Death01:18

Autophagic Cell Death

Christian de Duve discovered “autophagy,” a process in which cellular components are engulfed by membrane-bound organelles called autophagosomes. The autophagosomes then fuse with lysosomes to digest the enclosed contents. Autophagy is generally activated in cells to prevent cell death. However, cell death is triggered when the damage is beyond repair.
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and...
4.2K