Caspase-2 activity modulates AMP receptor trafficking and dendritic spine dynamics.A soluble tau fragment generated by caspase-2 is elevated in Alzheimer’s disease, Huntington's disease, and Lewy ...body disease and promotes cognitive defects.The genetic ablation of caspase-2 leads to symptomatic benefits in transgenic mice overexpressing mutant huntingtin or the amyloid-β precursor protein.Biallelic mutations in genes encoding p53-induced protein with a death domain 1, receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain cause intellectual, behavioral, and psychological abnormalities of varying severity, predominantly accompanied by pachygyria.Selective PIDDosome component inhibitors protect against neurotoxicity in in vitro models, which makes them promising therapeutic agents for the treatment of neurodegenerative diseases.
The PIDDosome is a multiprotein complex that includes p53-induced protein with a death domain 1 (PIDD1), receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD), and caspase-2, the activation of which is driven by PIDDosome assembly. In addition to the key role of the PIDDosome in the regulation of cell differentiation, tissue homeostasis, and organogenesis and regeneration, caspase-2, RAIDD and PIDD1 engagement in neuronal development was shown. Here, we focus on the involvement of PIDDosome components in neurodegenerative disorders, including retinal neuropathies, different types of brain damage, and Alzheimer’s disease (AD), Huntington’s disease (HD), and Lewy body disease. We also discuss pathogenic variants of PIDD1, RAIDD, and caspase-2 that are associated with intellectual, behavioral, and psychological abnormalities, together with prospective PIDDosome inhibition strategies and their potential clinical application.
The PIDDosome is a multiprotein complex that includes p53-induced protein with a death domain 1 (PIDD1), receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD), and caspase-2, the activation of which is driven by PIDDosome assembly. In addition to the key role of the PIDDosome in the regulation of cell differentiation, tissue homeostasis, and organogenesis and regeneration, caspase-2, RAIDD and PIDD1 engagement in neuronal development was shown. Here, we focus on the involvement of PIDDosome components in neurodegenerative disorders, including retinal neuropathies, different types of brain damage, and Alzheimer’s disease (AD), Huntington’s disease (HD), and Lewy body disease. We also discuss pathogenic variants of PIDD1, RAIDD, and caspase-2 that are associated with intellectual, behavioral, and psychological abnormalities, together with prospective PIDDosome inhibition strategies and their potential clinical application.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Caspase-2 belongs to the caspase family of proteins responsible for essential cellular functions including apoptosis and inflammation. Uniquely, caspase-2 has been identified as a tumor suppressor, ...but how it regulates this function is still unknown. For many years, caspase-2 has been considered an "orphan" caspase because, although it is able to induce apoptosis, there is an abundance of conflicting evidence that questions its necessity for apoptosis. Recent evidence supports that caspase-2 has non-apoptotic functions in the cell cycle and protection from genomic instability. It is unclear how caspase-2 regulates these opposing functions, which has made the mechanism of tumor suppression by caspase-2 difficult to determine. As a protease, caspase-2 likely exerts its functions by proteolytic cleavage of cellular substrates. This review highlights the known substrates of caspase-2 with a special focus on their functional relevance to caspase-2's role as a tumor suppressor.
The PIDDosome, which is an oligomeric signaling complex composed of PIDD, RAIDD and caspase-2, can induce proximity-based dimerization and activation of caspase-2. In the PIDDosome assembly, the ...adaptor protein RAIDD interacts with PIDD and caspase-2 via CARD:CARD and DD:DD, respectively. To analyze the PIDDosome assembly, we purified all of the DD superfamily members and performed biochemical analyses. The results revealed that caspase-2 CARD is an insoluble protein that can be solubilized by its binding partner, RAIDD CARD, but not by full-length RAIDD; this indicates that full-length RAIDD in closed states cannot interact with caspase-2 CARD. Moreover, we found that caspase-2 CARD can be solubilized and interact with full-length RAIDD in the presence of PIDD DD, indicating that PIDD DD initially binds to RAIDD, after which caspase-2 can be recruited to RAIDD via a CARD:CARD interaction. Our study will be useful in determining the order of assembly of the PIDDosome. BMB Reports 2013; 46(9): 471-476
PIDD mediates and stabilizes the interaction between RAIDD and Caspase-2 for the PIDDosome assembly Jang, T.H., School of Biotechnology and Graduate School of Biochemistry at Yeungnam University, Gyeongsan, Republic of Korea; Park, H.H., School of Biotechnology and Graduate School of Biochemistry at Yeungnam University, Gyeongsan, Republic of Korea
BMB reports,
09/2013, Volume:
46, Issue:
9
Journal Article
Peer reviewed
Open access
The PIDDosome, which is an oligomeric signaling complex composed of PIDD, RAIDD and caspase-2, can induce proximity-based dimerization and activation of caspase-2. In the PIDDosome assembly, the ...adaptor protein RAIDD interacts with PIDD and caspase-2 via CARD:CARD and DD:DD, respectively. To analyze the PIDDosome assembly, we purified all of the DD superfamily members and performed biochemical analyses. The results revealed that caspase-2 CARD is an insoluble protein that can be solubilized by its binding partner, RAIDD CARD, but not by full-length RAIDD; this indicates that full-length RAIDD in closed states cannot interact with caspase-2 CARD. Moreover, we found that caspase-2 CARD can be solubilized and interact with full-length RAIDD in the presence of PIDD DD, indicating that PIDD DD initially binds to RAIDD, after which caspase-2 can be recruited to RAIDD via a CARD:CARD interaction. Our study will be useful in determining the order of assembly of the PIDDosome
•
Caspase function
•
Caspase‐2: Initiator or executioner caspase?
•
Functions of caspase‐2
‐
Role in development
‐
Caspase‐2 in aging
‐
Caspase‐2 is a tumour suppressor
‐
Caspase‐2 substrates
...•
Measuring caspase‐2 activation during apoptosis
•
Caspase‐2 activation platforms
•
Regulation of caspase‐2 activation
‐
Inhibition of caspase‐2 by Hsp90α
‐
Caspase‐2 activity is suppressed by phosphorylation at distinct sites
‐
Alternatively spliced isoforms of caspase‐2
‐
Regulation of caspase‐2 during cell‐cycle
•
Caspase‐2 in disease
‐
Cancer
‐
Neurodegenerative disorders
‐
Ischemia‐reperfusion Injury
•
Concluding remarks
Caspase‐2 is the most evolutionarily conserved of all the caspases, yet it has a poorly defined role in apoptotic pathways. This is mainly due to a dearth of techniques to determine the activation status of caspase‐2 and the lack of an abnormal phenotype in caspase‐2 deficient mice. Nevertheless, emerging evidence suggests that caspase‐2 may have important functions in a number of stress‐induced cell death pathways, in cell cycle maintenance and regulation of tumour progression. This review discusses recent advances that have been made to help elucidate the true role of this elusive caspase and the potential contribution of caspase‐2 to the pathology of human diseases including cancer.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
P53-induced protein with a death domain (PIDD) has been described as primary p53 target gene, induced upon DNA damage. More than 10 years after its discovery, its physiological role in the DNA damage ...response remains enigmatic, as it seems to be able to execute life-death decisions in vitro, yet genetic ablation in mice failed to reveal an obvious phenotype. Nonetheless, evidence is accumulating that it contributes to the fine-tuning of the DNA-damage response by orchestrating critical processes such as caspase activation or nuclear factor κB translocation and can also exert additional nuclear functions, for example, the modulation of translesion synthesis. In this review, we aim to integrate these observations and propose possible unexplored functions of PIDD.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Despite being frequently mutated or deregulated in acute myeloid leukemia (AML) and many other cancers, the mechanisms by which nucleophosmin (NPM1) regulates oncogenesis remain elusive. We found ...that NPM1 plays a direct and conserved role in DNA damage-induced assembly of the PIDDosome complex, the activating platform for caspase-2. This function is carried in the nucleolus and is essential for caspase-2-mediated apoptosis in response to a variety of DNA injuries.
Neuronal apoptotic death generally requires de novo transcription, and activation of the transcription factor c-Jun has been shown to be necessary in multiple neuronal death paradigms. Caspase-2 has ...been implicated in death of neuronal and non-neuronal cells, but its relationship to transcriptional activation has not been clearly elucidated. In the present study, using two different neuronal apoptotic paradigms, β-amyloid treatment and NGF (nerve growth factor) withdrawal, we examined the hierarchical role of caspase-2 activation in the transcriptional control of neuron death. Both paradigms induce rapid activation of caspase-2 as well as activation of the transcription factor c-Jun and subsequent induction of the pro-apoptotic BH3 (Bcl-homology domain 3)-only protein Bim (Bcl-2-interacting mediator of cell death). Caspase-2 activation is dependent on the adaptor protein RAIDD {RIP (receptor-interacting protein)-associated ICH-1 ICE (interleukin-1β-converting enzyme)/CED-3 (cell-death determining 3) homologue 1 protein with a death domain}, and both caspase-2 and RAIDD are required for c-Jun activation and Bim induction. The present study thus shows that rapid caspase-2 activation is essential for c-Jun activation and Bim induction in neurons subjected to apoptotic stimuli. This places caspase-2 at an apical position in the apoptotic cascade and demonstrates for the first time that caspase-2 can regulate transcription.
A brief period of global brain ischemia, such as that induced by cardiac arrest or cardiopulmonary bypass surgery, causes cell death in vulnerable hippocampal CA1 pyramidal neurons days after ...reperfusion. Although numerous factors have been suggested to account for this phenomenon, the mechanisms underlying it are poorly understood. We describe a cell death signal called the PIDDosome, a protein complex of p53-induced protein with a death domain (PIDD), receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD), and procaspase-2. We induced 5 min of transient global cerebral ischemia (tGCI) using bilateral common carotid artery occlusion with hypotension. Western blot analysis showed that expression of twice-cleaved fragment of PIDD (PIDD-CC) increased in the cytosolic fraction of the hippocampal CA1 subregion and preceded procaspase-2 activation after tGCI. Caspase-2 cleaved Bid in brain homogenates. Co-immunoprecipitation and immunofluorescent studies demonstrated that PIDD-CC, RAIDD, and procaspase-2 were co-localized and bound directly, which indicates the formation of the PIDD death domain complex. Furthermore, we tested inhibition of PIDD expression by using small interfering RNA (siRNA) treatment that was initiated 48 h before tGCI. Administration of siRNA against PIDD decreased not only expression of PIDD-CC, but also activation of procaspase-2 and Bid, resulting in a decrease in histological neuronal damage and DNA fragmentation in the hippocampal CA1 subregion after tGCI. These results imply that PIDD plays an important role in procaspase-2 activation and delayed CA1 neuronal death after tGCI. We propose that PIDD is a hypothetical molecular target for therapy against neuronal death after tGCI.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Background/Aims: Viral infections represent a global health problem with the need for new viral therapies and better understanding of the immune response during infection. The most immediate and ...potent anti-viral defense mechanism is the production of type I interferon (IFN-I) which are activated rapidly following recognition of viral infection by host pathogen recognition receptors (PRR). The mechanisms of innate cellular signaling downstream of PRR activation remain to be fully understood. In the present study, we demonstrate that CASP2 and RIPK1 domain-containing adaptor with death domain (CRADD/RAIDD) is a critical component in type I IFN production. Methods: The role of RAIDD during IFN-I production was investigated using western blot, shRNA mediated lentiviral knockdown, immunoprecipitation and IFN-I driven dual luciferase assay. Results: Immunoprecipitation analysis revealed the molecular interaction of RAIDD with interferon regulatory factor 7 (IRF7) and its phosphorylating kinase IKKε. Using an IFN-4α driven dual luciferase analysis in RAIDD deficient cells, type I IFN activation by IKKε and IRF7 was dramatically reduced. Furthermore, deletion of either the caspase recruitment domain (CARD) or death domain (DD) of RAIDD inhibited IKKε and IRF7 mediated interferon-4α activation. Conclusion: We have identified that the adaptor molecule RAIDD coordinates IKKε and IRF7 interaction to ensure efficient expression of type I interferon.
PDF
