The PIDDosome, a Protein Complex Implicated in Activation of Caspase-2 in Response to Genotoxic Stress

  title={The PIDDosome, a Protein Complex Implicated in Activation of Caspase-2 in Response to Genotoxic Stress},
  author={Antoine Tinel and Jürg Tschopp},
  pages={843 - 846}
Apoptosis is triggered by activation of initiator caspases upon complex-mediated clustering of the inactive zymogen, as occurs in the caspase-9-activating apoptosome complex. [] Key Result We show that activation of caspase-2 occurs in a complex that contains the death domain-containing protein PIDD, whose expression is induced by p53, and the adaptor protein RAIDD. Increased PIDD expression resulted in spontaneous activation of caspase-2 and sensitization to apoptosis by genotoxic stimuli. Because PIDD…

Caspase-2 activation in the absence of PIDDosome formation

It is suggested that at least one alternative PIDDosome-independent mechanism of caspase-2 activation exists in mammals in response to DNA damage.

Essential Roles of the Bcl-2 Family of Proteins in Caspase-2-induced Apoptosis*

It is shown that proteolytic activation of Bid and the subsequent induction of the mitochondrial apoptotic pathway through Bax/Bak is essential for apoptosis triggered by caspase-2.

Functional connection between p53 and caspase-2 is essential for apoptosis induced by DNA damage

The results confirm the participation of PIDD and RAIDD in PIDDosome complex formation but question their role as sole mediators of caspase-2 activation.

Association of caspase-2 with the promyelocytic leukemia protein nuclear bodies

Evidence that caspase-2 is localized to the promyelocytic leukemia protein nuclear bodies (PML-NBs), nuclear macro-molecular complexes that are involved in many scenarios of apoptosis including DNA damage is presented.

DNA damage- and stress-induced apoptosis occurs independently of PIDD

It is reported that, although PIDD expression is inducible upon DNA damage, PIDD-deficient mice undergo apoptosis normally not only in response toDNA damage, but also inresponse to various p53-independent stress signals and to death receptor (DR) engagement, demonstrating that PIDD is not required for DNA damage-, stress-, and DR-induced apoptosis.

Structural Features of Caspase-Activating Complexes

  • H. H. Park
  • Biology, Chemistry
    International journal of molecular sciences
  • 2012
By analyzing the structural basis for the assembly mechanism of the caspase-activating complex, this work hopes to provide a comprehensive understanding of caspases activation by these important oligomeric complexes.

DNA damage-induced cell death : The role of caspase-2

It is proposed that MC is not a specific type of cell death but rather a pre-stage preceding cell death, suggesting that MC-related morphological changes are followed by activation of the apoptotic machinery.

PIDDosome-independent tumor suppression by Caspase-2

Pidd or Caspase-2 failed to suppress lymphoma formation triggered by γ-irradiation or 3-methylcholanthrene-driven fibrosarcoma development and Pidd deficiency associated with abnormal M-phase progression and delayed disease onset, indicating that both proteins are differentially engaged upon oncogenic stress triggered by c-Myc, leading to opposing effects on tumor-free survival.

A Novel Caspase-2 Complex Containing TRAF2 and RIP1*

It is demonstrated that endogenous caspase-2 is recruited into a large and inducible protein complex, together with TRAF2 and RIP1, that activates NF-κB and p38 MAPK through the caspases recruitment domain of casp enzyme-2 independently of its proteolytic activity.



A novel Apaf-1–independent putative caspase-2 activation complex

Gel filtration analysis of cell lysates shows that caspase-2 is spontaneously recruited to a large protein complex independent of cytochrome c and Apaf-1 and that recruitment of casp enzyme-2 to this complex is sufficient to mediate its activation.

Requirement for Caspase-2 in Stress-Induced Apoptosis Before Mitochondrial Permeabilization

It is argued that cytokine-induced and stress-induced apoptosis act through conceptually similar pathways in which mitochondria are amplifiers of caspase activity rather than initiators of cospase activation.

Caspase-2 Induces Apoptosis by Releasing Proapoptotic Proteins from Mitochondria*

It is shown that caspase-2 engages the mitochondria-dependent apoptotic pathway by inducing the release of cytochrome c (Cyt c) and other mitochondrial apoptogenic factors into the cell cytoplasm and it is found that Bcl-2 and BCl-xL can block caspases-2- and CRADD-induced cell death.

CRADD, a novel human apoptotic adaptor molecule for caspase-2, and FasL/tumor necrosis factor receptor-interacting protein RIP.

FADD/MORT1 is a death domain (DD)-containing adaptor/signaling molecule that interacts with the intracellular DD of FAS/APO-I (CD95) and tumor necrosis factor receptor 1 and the prodomain of

The Long Form of FLIP Is an Activator of Caspase-8 at the Fas Death-inducing Signaling Complex*

It is proposed that FLIPL inhibits caspase-8 release-dependent pro-apoptotic signals, whereas the single, membrane-restricted active site of theFLIPL-casp enzyme-inhibitory protein long form heterocomplex is proteolytically active and acts on local substrates such as RIP.

Many cuts to ruin: a comprehensive update of caspase substrates

This review summarizes the known caspase substrates comprising a bewildering list of more than 280 different proteins and highlights some recent aspects inferred by the cleavage of certain proteins in apoptosis.

Caspase-2 Acts Upstream of Mitochondria to Promote Cytochromec Release during Etoposide-induced Apoptosis*

Data indicate that caspase-2 provides an important link between etoposide-induced DNA damage and the engagement of the mitochondrial apoptotic pathway, and undermining caspases2 activity results in an attenuation of downstream events.

A unified model for apical caspase activation.

Pidd, a new death-domain–containing protein, is induced by p53 and promotes apoptosis

The data suggest that Pidd is an effector of p53-dependent apoptosis, and a new gene regulated by p53 that encodes a predicted protein of 915 amino acids in mice (910 amino acid in humans), which is named Pidd.