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Updated: Sep 28, 2025

Evaluation of Caspase Activation to Assess Innate Immune Cell Death
Published on: January 20, 2023
PIDD1 in cell cycle control, sterile inflammation and cell death
Elias S Weiler1, Tamas G Szabo1, Irmina Garcia-Carpio1
1Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
Abstract:
The death fold domain-containing protein PIDD1 has recently attracted renewed attention as a regulator of the orphan cell death-related protease, Caspase-2. Caspase-2 can activate p53 to promote cell cycle arrest in response to centrosome aberrations, and its activation requires formation of the PIDDosome multi-protein complex containing multimers of PIDD1 and the adapter RAIDD/CRADD at its core. However, PIDD1 appears to be able to engage with multiple client proteins to promote an even broader range of biological responses, such as NF-κB activation, translesion DNA synthesis or cell death. PIDD1 shows features of inteins, a class of self-cleaving proteins, to create different polypeptides from a common precursor protein that allow it to serve these diverse functions. This review summarizes structural information and molecular features as well as recent experimental advances that highlight the potential pathophysiological roles of this unique death fold protein to highlight its drug-target potential.
Insights
Death domain protein PIDD1 regulates Caspase-2 activation and cell death. Its unique intein-like features enable diverse functions, highlighting its potential as a drug target for various diseases.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- PIDD1 (death fold domain-containing protein) is a key regulator of Caspase-2, involved in cell death pathways.
- Caspase-2 activation, crucial for cell cycle arrest due to centrosome aberrations, depends on the PIDDosome complex.
- PIDD1 interacts with multiple proteins, influencing NF-κB activation, DNA synthesis, and cell death.
Purpose of the Study:
- To review structural and molecular features of PIDD1.
- To summarize recent advances in understanding PIDD1's diverse biological roles.
- To highlight PIDD1's potential as a drug target.
Main Methods:
- Literature review of structural and experimental data on PIDD1.
- Analysis of PIDD1's intein-like self-cleaving properties.
- Summary of studies on PIDD1's interactions and functions.
Main Results:
- PIDD1 forms the core of the PIDDosome complex with RAIDD/CRADD for Caspase-2 activation.
- PIDD1's intein-like mechanism allows generation of diverse polypeptides from a single precursor.
- PIDD1 participates in NF-κB activation, DNA repair, and cell death pathways.
Conclusions:
- PIDD1's unique self-cleaving mechanism underlies its diverse pathophysiological roles.
- PIDD1 represents a promising drug target due to its involvement in multiple cellular processes.
- Further research into PIDD1's structure-function relationships is warranted.
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