Related Experiment Video

Updated: Jun 14, 2026

Quantification of γH2AX Foci in Response to Ionising Radiation
06:53

Quantification of γH2AX Foci in Response to Ionising Radiation

Published on: April 6, 2010

AIF promotes chromatinolysis and caspase-independent programmed necrosis by interacting with histone H2AX

Cédric Artus1, Hanan Boujrad, Aïda Bouharrour

  • 1Centre de Recherche des Cordeliers, Paris, France.

The EMBO Journal
|April 3, 2010
PubMed

Insights

DNA alkylating agents trigger programmed necrosis via apoptosis-inducing factor (AIF). AIF interacts with histone H2AX in the nucleus, forming a complex with cyclophilin A (CypA) to degrade DNA and cause cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Programmed necrosis is a caspase-independent cell death pathway.
  • Apoptosis-inducing factor (AIF) mediates programmed necrosis induced by DNA alkylating agents.
  • The nuclear functions of AIF remain largely uncharacterized.

Purpose of the Study:

  • To elucidate the molecular mechanisms of AIF's nuclear action in programmed necrosis.
  • To identify key nuclear partners and motifs involved in AIF-mediated cell death.

Main Methods:

  • Investigated AIF interaction with nuclear proteins using deletion and mutagenesis of AIF's C-terminal proline-rich binding domain (PBD).
  • Assessed the role of histone H2AX and cyclophilin A (CypA) in AIF-induced chromatinolysis and programmed necrosis.
  • Analyzed H2AX phosphorylation at Ser139 following DNA alkylating agent treatment.

Main Results:

  • AIF directly binds to histone H2AX in the nucleus via its PBD.
  • This AIF-H2AX interaction is essential for forming a DNA-degrading complex with CypA, leading to chromatinolysis and programmed necrosis.
  • Genetic ablation of H2AX or downregulation of CypA confers resistance to programmed necrosis.
  • H2AX phosphorylation at Ser139 is critical for this cell death pathway.

Conclusions:

  • Histone H2AX is a crucial nuclear partner for AIF in programmed necrosis.
  • The AIF PBD acts as an apoptogenic motif, mediating interaction with H2AX and subsequent DNA degradation.
  • This study reveals novel insights into the mechanisms of programmed necrosis and the nuclear role of AIF.

More Related Videos

Identifying Caspases and their Motifs that Cleave Proteins During Influenza A Virus Infection08:16

Identifying Caspases and their Motifs that Cleave Proteins During Influenza A Virus Infection

Published on: July 21, 2022

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

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.
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...
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...
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.
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...
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...