Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Apr 29;50(2):813-824.
doi: 10.1042/BST20211186.

PIDD1 in cell cycle control, sterile inflammation and cell death

Elias S Weiler  1 , Tamas G Szabo  1 , Irmina Garcia-Carpio  1 , Andreas Villunger  1   2
Affiliations
Review

PIDD1 in cell cycle control, sterile inflammation and cell death

Elias S Weiler et al. Biochem Soc Trans. .

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.

Keywords: caspases; cell cycle; cell death; p53.

PubMed Disclaimer

Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1.
Figure 1.. Expression analysis of PIDDosome components, PIDD1, RAIDD, CASP2.
(A) Tissue-specific expression of H. sapiens PIDD1, RAIDD and CASP2 obtained from the Genotype-Tissue Expression (GTEx v8) project (https://www.gtexportal.org/). mRNA expression profiles are shown as log-transformed transcript per million (log(TPM)). (B) Correlation of PIDD1, RAIDD, and CASP2 gene expression (logTPM) in human tissues based on data from GTEx v8. Pearson's correlation coefficient shown as r-value.
Figure 2.
Figure 2.. PIDD1 auto-processing.
(A) Full length PIDD1 (FL-PIDD1) is processed into three different fragments. Auto-proteolytic cleavage between F445 and S446 produces PIDD1-N (48 kDa) and PIDD1-C (51 kDa). Further cleavage at S588 forms the PIDD1-CC (37 kDa) fragment. (B) Outline of the chemical transitions needed for PIDD1 auto-proteolysis. The same mechanism is supposed to occur to generate PIDD1-C and PIDD1-CC, in a sequential manner (please see main text for further details).
Figure 3.
Figure 3.. Biological functions of PIDD1-containing protein complexes.
DNA damage is reported to lead to activation of the Caspase-2 — and NEMO — PIDDosome, resulting in either mitochondrial cell death or pro-inflammatory NF-kB activation and cytokine expression. In response to supernumerary centrosomes, PIDDosome formation leads to p53 stabilization and p21-dependent cell cycle arrest. Under specific circumstances, e.g. after UV irradiation, PIDD1 associates with PCNA to promote Polη-mediated translesion DNA synthesis. Finally, interstrand DNA crosslinks (ICLs) that cannot be resolved in time trigger the formation of the Caspase-2 — PIDDosome via recruitment of PIDD1-CC to FANCI.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. van Opdenbosch, N. and Lamkanfi, M. (2019) Caspases in cell death, inflammation, and disease. Immunity 50, 1352–1364 10.1016/j.immuni.2019.05.020 - DOI - PMC - PubMed
    1. Yuan, J., Shaham, S., Ledoux, S., Ellis, H.M. and Horvitz, H.R. (1993) The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 75, 641–652 10.1016/0092-8674(93)90485-9 - DOI - PubMed
    1. Park, H.H., Lo, Y.-C., Lin, S.-C., Wang, L., Yang, J.K. and Wu, H. (2007) The death domain superfamily in intracellular signaling of apoptosis and inflammation. Annu. Rev. Immunol. 25, 561–586 10.1146/annurev.immunol.25.022106.141656 - DOI - PMC - PubMed
    1. Sohn, J. and Hur, S. (2016) Filament assemblies in foreign nucleic acid sensors. Curr. Opin. Struct. Biol. 37, 134–144 10.1016/j.sbi.2016.01.011 - DOI - PMC - PubMed
    1. Ramirez, M.L.G. and Salvesen, G.S. (2018) A primer on caspase mechanisms. Semin. Cell Dev. Biol. 82, 79–85 10.1016/j.semcdb.2018.01.002 - DOI - PMC - PubMed

Publication types

MeSH terms

Substances