Related Experiment Video

Updated: Jun 12, 2026

A Colorimetric Assay that Specifically Measures Granzyme B Proteolytic Activity: Hydrolysis of Boc-Ala-Ala-Asp-S-Bzl
05:20

A Colorimetric Assay that Specifically Measures Granzyme B Proteolytic Activity: Hydrolysis of Boc-Ala-Ala-Asp-S-Bzl

Published on: November 28, 2014

Granzyme A activates another way to die

Judy Lieberman1

  • 1Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA. lieberman@idi.harvard.edu

Immunological Reviews
|June 12, 2010
PubMed

Insights

Granzyme A (GzmA) initiates a unique cell death pathway by damaging mitochondria and DNA. This pathway is effective against cells resistant to other death signals, offering enhanced protection.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Granzyme A (GzmA) is a key serine protease found in cytotoxic granules of immune cells.
  • GzmA plays a crucial role in cell-mediated cytotoxicity and immune surveillance.
  • Understanding GzmA's mechanisms is vital for developing novel therapeutic strategies.

Purpose of the Study:

  • To elucidate the novel programmed cell death pathway initiated by Granzyme A.
  • To investigate the molecular targets and mechanisms of GzmA-induced cell death.
  • To explore GzmA's role in overcoming resistance to other cell death pathways and its proinflammatory effects.

Main Methods:

  • Analysis of GzmA's effects on mitochondrial function and cellular metabolism.
  • Investigation of GzmA's impact on nuclear proteins and DNA integrity.
  • Assessment of cellular sensitivity to GzmA in the context of resistance to caspases or Granzyme B.

Main Results:

  • GzmA cleaves NDUFS3 in electron transport complex I, disrupting mitochondrial metabolism and generating reactive oxygen species (ROS).
  • ROS facilitates nuclear translocation of the SET complex, leading to single-stranded DNA damage.
  • GzmA degrades histones, lamins, and DNA repair proteins (Ku70, PARP-1), inducing cell death.
  • Cells resistant to caspases or GzmB are sensitive to GzmA, highlighting its distinct cytotoxic mechanism.
  • GzmA exhibits proinflammatory activity by activating pro-interleukin-1beta.

Conclusions:

  • GzmA activates a unique, multi-pronged cell death pathway involving mitochondrial dysfunction, ROS generation, and nuclear damage.
  • This pathway effectively eliminates cells resistant to conventional apoptotic or cytotoxic mechanisms.
  • GzmA's distinct mode of action and proinflammatory potential offer new avenues for therapeutic intervention in cancer and infectious diseases.

More Related Videos

A High Yield and Cost-efficient Expression System of Human Granzymes in Mammalian Cells09:16

A High Yield and Cost-efficient Expression System of Human Granzymes in Mammalian Cells

Published on: June 10, 2015

Neutrophil Lifespan Extension with CLON-G and an In Vitro Spontaneous Death Assay05:52

Neutrophil Lifespan Extension with CLON-G and an In Vitro Spontaneous Death Assay

Published on: May 12, 2023

Related Concept Videos

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.
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.
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...
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 pro-apoptotic...