Affinage

PIDD1

PIDD1 alternative open reading frame protein · UniProt C0HMD6

Length
171 aa
Mass
16.6 kDa
Annotated
2026-06-10
49 papers in source corpus 27 papers cited in narrative 28 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIDD1 is a p53-inducible death-domain/leucine-rich-repeat scaffold that converts genotoxic and centrosomal stress signals into discrete pro-survival or pro-death outputs by nucleating two alternative PIDDosome complexes (PMID:10973264, PMID:17159900). The full-length protein undergoes constitutive intein-like autoproteolysis at S446 (yielding PIDD-C) and S588 (yielding PIDD-CC), a maturation step requiring Hsp90/p23 chaperoning of cytoplasmic PIDD1; the resulting fragments dictate downstream specificity, with PIDD-C recruiting RIP1 and NEMO to drive NF-κB activation and PIDD-CC engaging the adaptor RAIDD to activate caspase-2 (PMID:17159900, PMID:20966961, PMID:16360037, PMID:16183742). Partner selection at the death domain is set by a stepwise PTM cascade: ATM/ATR phosphorylation of T788 licenses RAIDD binding and PIAS1-mediated SUMO-1 conjugation at K879 (reversed by SENP3), which compartmentalizes nascent PIDDosomes at nucleolar RAIDD via a SUMO-interacting motif, followed by PARP4-catalyzed ADP-ribosylation of E783 that is dispensable for caspase-2 recruitment but essential for its dimerization and activation (PMID:22854598, PMID:39448602, PMID:42054439). The same caspase-2 arm is mobilized in response to centrosome amplification, where the centriolar distal-appendage protein ANKRD26 recruits PIDD1 to mother centrioles to trigger PIDDosome assembly, NF-κB-driven sterile inflammation, and control of hepatocyte/cardiomyocyte ploidy (PMID:33350495, PMID:37530438). Beyond cell death, PIDD1 promotes translesion synthesis by modulating p21–PCNA dissociation and PCNA monoubiquitination, recruits DNA-PKcs to stalled forks to enable ATR signaling, and stabilizes NRF2 by sequestering KEAP1 to drive chemoresistance (PMID:21415862, PMID:29309644, PMID:31455821). Biallelic death-domain mutations that abolish PIDD1–RAIDD/CRADD interaction and PIDDosome function cause human intellectual disability (PMID:33414379).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 High

    Established PIDD1 as a transcriptional effector of p53 in DNA-damage-induced apoptosis, placing it downstream of the central tumor suppressor.

    Evidence p53 consensus reporter assay, antisense knockdown, and IR induction in p53+/+ vs p53-/- cells

    PMID:10973264

    Open questions at the time
    • No molecular mechanism of how the protein executes apoptosis
    • Effector partners unidentified
  2. 2000 Medium

    Defined the LRR–death-domain architecture and showed the protein is proteolytically processed and engages death-domain partners, hinting at a scaffolding role.

    Evidence Cloning, Co-IP with FADD and MADD, Western blot of processing fragments

    PMID:10825539

    Open questions at the time
    • Functional consequence of FADD/MADD binding untested
    • Processing mechanism unknown
  3. 2005 High

    Identified RAIDD and caspase-2 as the essential downstream apoptotic module and revealed a parallel nuclear RIP1/NEMO complex driving NF-κB, establishing PIDD1 as a bifurcating stress hub.

    Evidence RAIDD-/- and caspase-2-/- MEFs, reciprocal Co-IP, RNAi, NEMO modification and NF-κB reporter assays

    PMID:16183742 PMID:16360037

    Open questions at the time
    • What determines NF-κB vs apoptosis choice not resolved
    • Stoichiometry and assembly order undefined
  4. 2006 High

    Showed autoproteolysis at S446 and S588 generates PIDD-C and PIDD-CC fragments whose differential generation dictates NF-κB versus caspase-2 output, providing the molecular basis for output switching.

    Evidence Active-site mutagenesis of cleavage sites, fragment Western blots, NF-κB/caspase-2 readouts, fractionation; plus nucleolar/nucleolin colocalization

    PMID:16982033 PMID:17159900

    Open questions at the time
    • What regulates relative fragment abundance not established here
    • Functional role of nucleolin binding unclear
  5. 2010 High

    Identified Hsp90/p23 as the chaperone required for PIDD1 maturation, defining an upstream checkpoint that gates both downstream arms.

    Evidence Co-IP, geldanamycin inhibition, fragment Western blot, NF-κB and caspase-2 assays, fractionation

    PMID:20966961

    Open questions at the time
    • How Hsp90 release is triggered upon PIDDosome formation unclear
  6. 2011 High

    Revealed a non-apoptotic genome-maintenance function: PIDD1 binds PCNA to promote translesion synthesis via p21-PCNA dissociation and PCNA monoubiquitination.

    Evidence Proteomics, Co-IP, PCNA ubiquitination and TLS assays, PIDD-deficient cells and mice, UV survival

    PMID:21415862

    Open questions at the time
    • Whether this requires PIDDosome fragments not defined
    • Relation to caspase-2 arm unclear
  7. 2012 High

    Showed ATM phosphorylation of T788 within the death domain is the switch that licenses RAIDD binding/caspase-2 activation versus default RIP1/NF-κB engagement, mechanistically linking damage sensing to fate choice.

    Evidence Phospho-specific antibody, T788 mutagenesis, ATM kinase assay, Co-IP, caspase-2 and Chk1-suppressed pathway epistasis

    PMID:22854598

    Open questions at the time
    • Additional PTMs downstream of T788 not yet known at this stage
  8. 2009 High

    Genetic knockout showed PIDD1 is dispensable for canonical DNA-damage and death-receptor apoptosis in vivo, narrowing its essential role to NF-κB and context-specific functions.

    Evidence PIDD knockout mice, multi-stimulus apoptosis assays, caspase-2 processing Western blot

    PMID:19575295

    Open questions at the time
    • Reconciliation with prior overexpression apoptosis data incomplete
    • Tissue-specific roles untested here
  9. 2012 High

    Defined PIDD1 as rate-limiting for DNA-damage-induced NF-κB/cytokine signaling and dispensable for survival, and showed neuronal caspase-2 death uses RAIDD independently of PIDD1, sharpening which contexts require the scaffold.

    Evidence PIDD knockout cells, NF-κB reporter, cytokine ELISA, lymphoma model; PIDD/RAIDD-null neurons with caspase-2 assays

    PMID:22515271 PMID:23238565

    Open questions at the time
    • Mechanism of PIDD-independent RAIDD-caspase-2 activation in neurons unknown
  10. 2013 Medium

    Reconstituted the ordered PIDDosome assembly hierarchy (PIDD DD → RAIDD → caspase-2 CARD), explaining how the scaffold organizes the apoptotic platform.

    Evidence Recombinant proteins, solubilization and pull-down assays, gel filtration, dominant-negative mutants

    PMID:20406701 PMID:24064063

    Open questions at the time
    • In-cell relevance of in vitro assembly order not tested
    • Single-lab reconstitution
  11. 2017 Medium

    Showed Pidd1 promotes Eμ-Myc lymphomagenesis independently of RAIDD/PIDDosome, demonstrating a tumor-promoting function uncoupled from caspase-2 death.

    Evidence Eμ-Myc/Raidd-/- and Pidd1-/- mice, tumor-free survival, genetic epistasis

    PMID:25857265

    Open questions at the time
    • Molecular basis of RAIDD-independent tumor promotion unidentified
  12. 2019 High

    Established two additional non-apoptotic roles: recruiting DNA-PKcs to stalled forks to enable ATR signaling, and sequestering KEAP1 to stabilize NRF2 and confer chemoresistance.

    Evidence Co-IP and domain mapping, chromatin fractionation, ATR-Chk1 assays; KEAP1 Co-IP, NRF2 ubiquitination/stability, xenograft

    PMID:29309644 PMID:31455821

    Open questions at the time
    • Whether these depend on PIDD1 processing/PTMs unclear
    • Integration with PIDDosome arm undefined
  13. 2020 High

    Identified ANKRD26 as the centriolar receptor that recruits PIDD1 to distal appendages, defining the structural basis for centrosome-amplification sensing by the PIDDosome.

    Evidence Genome-wide screen, Co-IP, microscopy of PIDD1 at distal appendages, ANKRD26 knockdown/mutation, caspase-2 readout

    PMID:33350495

    Open questions at the time
    • How extra centrioles are counted into a PIDD1 signal not fully resolved
  14. 2021 High

    Linked PIDD1 death-domain mutations that abolish RAIDD/CRADD binding and PIDDosome function to human intellectual disability, establishing physiological importance of the apoptotic scaffold.

    Evidence Co-IP, co-localization, genome-edited PIDDosome reporter lines, patient family genetics

    PMID:33414379 PMID:36689811

    Open questions at the time
    • Neurodevelopmental mechanism downstream of lost PIDDosome unknown
  15. 2023 High

    Showed centrosome amplification triggers a NEMO-PIDDosome NF-κB program producing sterile inflammation and immune surveillance, broadening PIDD1's role from cell-intrinsic to paracrine.

    Evidence Centrosome amplification models, NEMO-PIDDosome Co-IP, cytokine profiling, macrophage polarization and NK-killing assays, ANKRD26 knockdown

    PMID:37530438

    Open questions at the time
    • In vivo contribution to tumor immunosurveillance not fully established
  16. 2024 High

    Defined a SUMO-dependent compartmentalization step: ATR-phospho-T788 enables PIAS1 SUMOylation at K879 (reversed by SENP3), captured by nucleolar RAIDD via a SIM to complete PIDDosome assembly for caspase-2.

    Evidence SUMOylation assays, K879 mutagenesis, ATR kinase assays, PIAS1/SENP3 manipulation, nucleolar fractionation, ICL apoptosis assay

    PMID:39448602

    Open questions at the time
    • Why nucleolar compartmentalization is required mechanistically only partly resolved
  17. 2024 Medium

    Identified m6A/YTHDF2-mediated decay of PIDD1 mRNA as a post-transcriptional brake on PIDDosome-driven apoptosis in arsenic-exposed cells.

    Evidence m6A-RIP, RNA pulldown, YTHDF2 knockdown, PIDDosome Western blots, caspase-2 and apoptosis assays

    PMID:39675544

    Open questions at the time
    • Single-lab, context-restricted to keratinocytes
    • Physiological breadth untested
  18. 2026 High

    Completed the PTM cascade by showing PARP4-catalyzed ADP-ribosylation of E783 (downstream of SUMOylation, reversed by PARP14) is the terminal step essential for caspase-2 dimerization and activation.

    Evidence In vitro ADPr assays, PARP4/PARP14 manipulation, E783 mutagenesis, caspase-2 dimerization and ICL apoptosis assays

    PMID:42054439

    Open questions at the time
    • Structural mechanism of how E783-ADPr drives dimerization undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PIDD1's apoptotic scaffolding, NF-κB inflammatory, and genome-maintenance/NRF2 functions are coordinately regulated within a single cell, and which arm underlies its developmental ploidy control and neurodevelopmental disease, remains unresolved.
  • No integrated model linking fragment stoichiometry, PTM state, and subcellular localization to fate choice
  • Mechanism connecting PIDDosome loss to intellectual disability unknown
  • Peer-reviewed confirmation of in vivo ploidy-control roles pending

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005634 nucleus 2 GO:0005730 nucleolus 2 GO:0005815 microtubule organizing center 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-73894 DNA Repair 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ANKRD26CRADDHSP90IKBKGKEAP1PCNAPRKDCRIPK1
Complex memberships
NEMO-PIDDosome (PIDD1/RIPK1/NEMO)PIDDosome (PIDD1/RAIDD/caspase-2)

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 PIDD1 (Pidd) is a p53 target gene transcriptionally induced by p53 binding to a consensus element upstream of the coding region; overexpression inhibits cell growth by inducing apoptosis, and antisense inhibition of PIDD attenuates p53-mediated apoptosis. Reporter assay with p53 consensus element, antisense knockdown, overexpression in cells, ionizing radiation induction in p53+/+ vs p53-/- cells Nature genetics High 10973264
2000 LRDD/PIDD1 protein contains N-terminal leucine-rich repeats (LRRs) and a C-terminal death domain (DD), is processed into ~33 kDa and ~55 kDa fragments, and interacts with death-domain-containing proteins FADD and MADD through its death domain. Cloning, co-immunoprecipitation, Western blot of processing fragments Biochimica et biophysica acta Medium 10825539
2005 PIDD1-induced apoptosis and growth suppression require the adaptor protein RAIDD; PIDD is a cytoplasmic protein whose cell death activity is associated with early caspase-2 activation followed by caspase-3 and -7 activation. RAIDD-/- and caspase-2-/- MEFs, overexpression, caspase activity assays, cytochrome c release, subcellular fractionation Proceedings of the National Academy of Sciences of the United States of America High 16183742
2005 In response to genotoxic stress, PIDD1 forms a nuclear complex with the kinase RIP1 and NEMO, enhancing sumoylation and ubiquitination of NEMO to activate NF-κB; depletion of PIDD1 or RIP1 (but not caspase-2) abrogates this NEMO modification and NF-κB activation. Co-immunoprecipitation, RNAi knockdown, NEMO sumoylation/ubiquitination assays, NF-κB reporter Cell High 16360037
2006 PIDD1 undergoes constitutive autoproteolysis at S446 to generate PIDD-C (51 kDa) and at S588 to generate PIDD-CC (37 kDa) by an intein-like mechanism; PIDD-C mediates NF-κB activation via RIP1/NEMO recruitment, while PIDD-CC triggers caspase-2 activation and apoptosis; a non-cleavable PIDD mutant cannot translocate to the nucleus and loses both activities. Site-directed mutagenesis of cleavage sites, Western blot of processing fragments, NF-κB reporter, caspase-2 activation assays, nuclear/cytoplasmic fractionation The EMBO journal High 17159900
2006 After intracellular processing, the C-terminal death domain-containing fragment of PIDD1 translocates to nucleoli and interacts with nucleolin; the PIDD death domain alone tends to form filamentous structures; overexpression of full-length PIDD or the DD sensitizes cells to UV-induced apoptosis. Co-localization by fluorescence microscopy, co-immunoprecipitation of PIDD DD with nucleolin, overexpression assays Biochemical and biophysical research communications Medium 16982033
2007 Three PIDD1 isoforms are differentially expressed; only isoform 1 (full-length) interacts with RAIDD and activates caspase-2; all three isoforms can activate NF-κB in response to genotoxic stress; isoform 2 counteracts pro-apoptotic function of isoform 1 while isoform 3 enhances it. RT-PCR of isoforms, co-immunoprecipitation with RAIDD, NF-κB reporter, caspase-2 activation assays, overexpression Oncogene Medium 17637755
2007 The PIDD DD and RAIDD DD form an oligomeric complex of ~150 kDa in solution; crystals of the complex were obtained in space group P6(5), initiating structural characterization of the PIDDosome core. Recombinant protein purification, gel filtration, multi-angle light scattering (MALS), X-ray crystallography (3.2 Å resolution) Acta crystallographica Section F Medium 17329820
2008 RNAi silencing of PIDD1 suppresses caspase-2 activation and apoptosis induced by both wild-type p53 and the transactivation-deficient p53(Q22/S23) mutant, placing PIDD1 upstream of caspase-2 in an early DNA damage-facilitated apoptotic pathway; cytochrome c release and cell death require PIDD and caspase-2. RNAi knockdown of PIDD, cytochrome c release assay, sub-G1 DNA content, nuclear fragmentation, inducible p53 expression system Proceedings of the National Academy of Sciences of the United States of America Medium 18238895
2009 PIDD1-deficient mice undergo normal apoptosis in response to DNA damage, various stress signals, and death receptor engagement; caspase-2 processing and activation occur normally in PIDD-null cells after DNA damage, demonstrating that PIDD1 is dispensable for these apoptotic pathways in vivo. PIDD knockout mouse generation, apoptosis assays (multiple stimuli), caspase-2 processing Western blot Apoptosis High 19575295
2010 Hsp90 (together with co-chaperone p23) binds PIDD1 and is required for PIDD1 autoproteolytic processing; inhibition of Hsp90 with geldanamycin disrupts PIDD-Hsp90 association, impairs PIDD-C and PIDD-CC generation, and abrogates both NF-κB activation and caspase-2 activation; Hsp90 is released upon PIDDosome formation; only cytoplasmic PIDD is Hsp90-bound, while nuclear PIDD is active. Co-immunoprecipitation, geldanamycin inhibition, Western blot of processing fragments, NF-κB reporter, caspase-2 activation, nuclear/cytoplasmic fractionation Cell death and differentiation High 20966961
2010 Point mutations R147E in RAIDD and Y814A in PIDD1 act as dominant negatives to prevent PIDDosome assembly; PIDDosome assembly is time-dependent and salt-concentration-dependent; these dominant negative effects cannot be applied after the PIDDosome has already formed. Recombinant protein purification, dominant-negative mutagenesis, biochemical PIDDosome assembly assays Biochimica et biophysica acta Medium 20406701
2011 PIDD1 interacts with PCNA (identified by proteomics) and modulates p21-PCNA dissociation, promotes PCNA monoubiquitination, and facilitates interaction of PCNA with TLS polymerase eta in response to UV irradiation; PIDD deficiency impairs translesion synthesis (TLS) both in vitro and in vivo and sensitizes cells to UV-induced apoptosis. Proteomics screen, co-immunoprecipitation, PCNA ubiquitination assay, TLS assay, PIDD-deficient cells and mice, UV survival assay Cell death and differentiation High 21415862
2012 ATM phosphorylates PIDD1 on Thr788 within the death domain in response to DNA damage; this phosphorylation is necessary and sufficient for RAIDD binding and caspase-2 activation (PIDDosome assembly); non-phosphorylatable PIDD fails to bind RAIDD or activate caspase-2 and instead engages RIP1 for pro-survival NF-κB signaling; the PIDDosome functions in the ATM/ATR-caspase-2 'Chk1-suppressed' apoptotic pathway. Phospho-specific antibody, site-directed mutagenesis of T788, Co-IP, caspase-2 activation assay, Chk1 inhibition, ATM kinase assay, genetic epistasis Molecular cell High 22854598
2012 PIDD1 loss limits NF-κB activation and cytokine release after DNA damage but does not affect cell survival or clonal growth; PIDD is rate-limiting for DNA-damage-induced NF-κB signaling; loss of PIDD does not affect IR-driven lymphomagenesis. PIDD knockout MEFs and hematopoietic cells, NF-κB reporter, cytokine ELISA, γ-irradiation lymphoma model Cell death and differentiation High 23238565
2012 In neurons, caspase-2 activation induced by NGF deprivation or Aβ requires RAIDD but is independent of PIDD expression; PIDD-null neurons form RAIDD-caspase-2 complexes normally; neuronal caspase-2-dependent death requires RAIDD but not PIDD. PIDD-null and RAIDD-null neurons, caspase-2 activity assay, Co-IP of caspase-2/RAIDD complex, NGF deprivation and Aβ treatment The Biochemical journal High 22515271
2013 PIDD1 death domain initially binds RAIDD, after which caspase-2 is recruited to RAIDD via CARD:CARD interaction; caspase-2 CARD is insoluble alone but solubilized by RAIDD CARD binding; full-length RAIDD in closed state cannot interact with caspase-2 CARD unless PIDD DD is present, defining the order of PIDDosome assembly. Recombinant protein purification, solubilization assay, biochemical binding/pull-down, size-exclusion chromatography BMB reports Medium 24064063
2015 In the Eμ-Myc lymphoma model, Pidd1 acts as a tumor promoter (loss delays lymphoma onset) independently of its ability to interact with Raidd scaffold, indicating Pidd1's oncogenic/tumor-promoting role is uncoupled from PIDDosome-mediated caspase-2 activation. Eμ-Myc/Raidd-/- and Pidd1-/- mice, tumor-free survival analysis, genetic epistasis Cell death and differentiation Medium 25857265
2018 PIDD1 is required to recruit DNA-PKcs to stalled replication forks through direct binding to the N-terminal region of DNA-PKcs; this interaction is needed for ATR association with DNA-PKcs, ATR signaling pathway activation, intra-S-phase checkpoint, and cellular resistance to replication stress. Co-immunoprecipitation, PIDD knockdown, DNA-PKcs recruitment to stalled forks (chromatin fractionation), ATR-Chk1 signaling assays, domain mapping Nucleic acids research High 29309644
2019 PIDD1 interacts with KEAP1 and competitively sequesters it from NRF2, reducing NRF2 ubiquitination and increasing NRF2 protein stability; PIDD promotes chemoresistance in NSCLC cells in an NRF2-dependent manner both in vitro and in vivo. Co-immunoprecipitation of PIDD-KEAP1, NRF2 ubiquitination assay, NRF2 stability assays, PIDD knockdown/overexpression with chemosensitivity assays, xenograft in vivo model Scientific reports High 31455821
2020 The centriolar distal appendage protein ANKRD26 interacts with and recruits PIDD1 to centriole distal appendages; this localization is required for PIDDosome activation following centrosome amplification; a recurrent ANKRD26 tumor mutation disrupts PIDD1 localization and PIDDosome activation. Genome-wide screen, Co-immunoprecipitation, fluorescence microscopy of PIDD1 at distal appendages, ANKRD26 knockdown/mutation, PIDDosome activation assay (caspase-2) The EMBO journal High 33350495
2021 Biallelic mutations in the PIDD1 death domain (Gln863*, Arg815Trp) prevent co-localization and co-precipitation with CRADD/RAIDD in HEK293 cells, causing CRADD aggregation and mis-localization, and abolish PIDDosome function in genome-edited cell lines; these mutations cause intellectual disability in humans. Co-immunoprecipitation, fluorescence co-localization, genome-edited PIDDosome reporter cell lines, exon trap for splice mutation Translational psychiatry High 33414379
2023 Extra centrosomes trigger PIDDosome-dependent NF-κB signaling and sterile inflammation through a NEMO-PIDDosome (PIDD1/RIPK1/NEMO); this induces a paracrine chemokine/cytokine profile that polarizes macrophages to a pro-inflammatory phenotype and increases cancer cell susceptibility to NK-cell attack; ANKRD26 at centriole distal appendages is required for PIDD1 recruitment and this NF-κB response. Centrosome amplification models (cytokinesis failure, centriole overduplication), NF-κB reporter, PIDD1/RIPK1/NEMO Co-IP, cytokine profiling, macrophage polarization assay, NK-cell killing assay, ANKRD26 knockdown The EMBO journal High 37530438
2024 DNA damage-induced monoSUMOylation of PIDD1 at K879 in the death domain, catalyzed by PIAS1 and reversed by SENP3, is triggered by ATR phosphorylation of T788; phospho-PIDD1 enables PIAS1 docking for SUMO-1 conjugation; SUMO-PIDD1 is captured by nucleolar RAIDD via a SUMO-interacting motif (SIM) in the RAIDD DD to compartmentalize nascent PIDDosomes for caspase-2 recruitment; denying SUMOylation or SUMO-SIM interaction blocks PIDDosome completion and eliminates apoptotic response to ICL repair failure. SUMOylation assays, site-directed mutagenesis of K879, ATR kinase assays, PIAS1/SENP3 manipulation, Co-IP, nucleolar fractionation, caspase-2 activation assay, ICL-induced apoptosis assay Nature communications High 39448602
2023 Pathogenic variants R815W, R862W, and Q863stop in the PIDD1 death domain prevent interaction between PIDD1 and RAIDD, thereby disrupting PIDDosome formation and caspase-2 activation. Co-immunoprecipitation, PIDDosome assembly assay, caspase-2 activation assay with mutant PIDD1 constructs Biochemical and biophysical research communications Medium 36689811
2024 YTHDF2 binds PIDD1 mRNA in an m6A-dependent manner and promotes its degradation, reducing PIDD1 protein levels, PIDDosome complex formation, caspase-2 activation, and mitochondrial apoptosis in arsenic-exposed keratinocytes. m6A-RIP, RNA pulldown, YTHDF2 knockdown, Western blot of PIDD1 and PIDDosome components, caspase-2 activity assay, apoptosis assay Chemico-biological interactions Medium 39675544
2026 PARP4 ADP-ribosylates PIDD1 at conserved E783 in the death domain; this modification is catalyzed by PARP4 (previously orphan PARP) and reversed by PARP14 ribosylhydrolase activity; ADPr is triggered by ATR phosphorylation-induced PIAS1-mediated SUMOylation of the PIDD1 DD (SUMO enables PARP4 docking); E783 ADPr is dispensable for RAIDD and caspase-2 recruitment but essential for caspase-2 dimerization; denial of E783 ADPr eliminates caspase-2 activation and apoptosis in response to ICL repair failure. ADP-ribosylation assays, PARP4/PARP14 manipulation, site-directed mutagenesis of E783, PIDD1 domain biochemistry, caspase-2 dimerization assay, ICL-induced apoptosis assay Science advances High 42054439
2025 Sequential and quantitative autoproteolytic processing of PIDD1 is required for PIDDosome-mediated control of hepatocyte and cardiomyocyte ploidy during postnatal organ development; stoichiometric imbalance in PIDD1-C vs PIDD1-CC fragments impairs p53-dependent and -independent cell cycle arrest and caspase-2-dependent apoptosis caused by centrosome amplification; ANKRD26 is required for PIDD1 targeting to mother centrioles for PIDDosome activation in cardiomyocytes in a p53-independent, p21-dependent manner. Targeted mutagenesis of autoproteolytic sites in mice, DNA content analysis (flow cytometry), genetic deletion of PIDDosome components, nuclear RNA sequencing, Mdm2 caspase cleavage motif mutagenesis bioRxivpreprint Medium

Source papers

Stage 0 corpus · 49 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 PIDD mediates NF-kappaB activation in response to DNA damage. Cell 286 16360037
2000 Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis. Nature genetics 264 10973264
2006 Autoproteolysis of PIDD marks the bifurcation between pro-death caspase-2 and pro-survival NF-kappaB pathway. The EMBO journal 138 17159900
2021 Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability. Translational psychiatry 96 33414379
2005 Apoptosis caused by p53-induced protein with death domain (PIDD) depends on the death adapter protein RAIDD. Proceedings of the National Academy of Sciences of the United States of America 89 16183742
2012 PIDD death-domain phosphorylation by ATM controls prodeath versus prosurvival PIDDosome signaling. Molecular cell 78 22854598
2008 A role for caspase 2 and PIDD in the process of p53-mediated apoptosis. Proceedings of the National Academy of Sciences of the United States of America 68 18238895
2020 ANKRD26 recruits PIDD1 to centriolar distal appendages to activate the PIDDosome following centrosome amplification. The EMBO journal 63 33350495
2000 LRDD, a novel leucine rich repeat and death domain containing protein. Biochimica et biophysica acta 52 10825539
2007 p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress. Oncogene 51 17637755
2016 Crocetin exploits p53-induced death domain (PIDD) and FAS-associated death domain (FADD) proteins to induce apoptosis in colorectal cancer. Scientific reports 43 27622714
2009 DNA damage- and stress-induced apoptosis occurs independently of PIDD. Apoptosis : an international journal on programmed cell death 42 19575295
2012 Neuronal caspase 2 activity and function requires RAIDD, but not PIDD. The Biochemical journal 35 22515271
2022 PIDD1 in cell cycle control, sterile inflammation and cell death. Biochemical Society transactions 29 35343572
2005 PIDD: a switch hitter. Cell 28 16360026
2012 P53-induced protein with a death domain (PIDD): master of puppets? Oncogene 26 22266869
2012 Loss of PIDD limits NF-κB activation and cytokine production but not cell survival or transformation after DNA damage. Cell death and differentiation 25 23238565
2006 Upon intracellular processing, the C-terminal death domain-containing fragment of the p53-inducible PIDD/LRDD protein translocates to the nucleoli and interacts with nucleolin. Biochemical and biophysical research communications 24 16982033
2023 Extra centrosomes induce PIDD1-mediated inflammation and immunosurveillance. The EMBO journal 22 37530438
2018 PIDD mediates the association of DNA-PKcs and ATR at stalled replication forks to facilitate the ATR signaling pathway. Nucleic acids research 21 29309644
2011 PIDD orchestrates translesion DNA synthesis in response to UV irradiation. Cell death and differentiation 21 21415862
2015 The tumor-modulatory effects of Caspase-2 and Pidd1 do not require the scaffold protein Raidd. Cell death and differentiation 20 25857265
2021 Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features. European journal of human genetics : EJHG 18 34163010
2017 Iodine-131 induces apoptosis in human cardiac muscle cells through the p53/Bax/caspase-3 and PIDD/caspase-2/ t‑BID/cytochrome c/caspase-3 signaling pathway. Oncology reports 18 28714021
2019 PIDD interaction with KEAP1 as a new mutation-independent mechanism to promote NRF2 stabilization and chemoresistance in NSCLC. Scientific reports 16 31455821
2013 Involvement of upregulated p53-induced death domain protein (PIDD) in neuronal apoptosis after rat traumatic brain injury. Journal of molecular neuroscience : MN 16 23797734
2007 The expression of p53-induced protein with death domain (Pidd) and apoptosis in oral squamous cell carcinoma. British journal of cancer 15 17437012
2013 PIDD mediates and stabilizes the interaction between RAIDD and caspase-2 for the PIDDosome assembly. BMB reports 14 24064063
2007 Crystallization and preliminary X-ray crystallographic studies of the oligomeric death-domain complex between PIDD and RAIDD. Acta crystallographica. Section F, Structural biology and crystallization communications 14 17329820
2010 Identification and analysis of dominant negative mutants of RAIDD and PIDD. Biochimica et biophysica acta 13 20406701
2010 Regulation of PIDD auto-proteolysis and activity by the molecular chaperone Hsp90. Cell death and differentiation 13 20966961
2016 PIDD Mediates Radiation-Induced Microglia Activation. Radiation research 12 27643878
2016 E1A enhances cellular sensitivity to DNA-damage-induced apoptosis through PIDD-dependent caspase-2 activation. Cell death discovery 10 27833761
2011 A single-center study of hematopoietic stem cell transplantation for primary immune deficiencies (PIDD). Pediatric transplantation 10 22093026
2022 Serum Autoantibodies against LRDD, STC1, and FOXA1 as Biomarkers in the Detection of Ovarian Cancer. Disease markers 9 35273656
2016 Rescuing neuronal cell death by RAIDD- and PIDD- derived peptides and its implications for therapeutic intervention in neurodegenerative diseases. Scientific reports 8 27502430
2011 PIDD4, a novel PIDD isoform without the LRR domain, can independently induce cell apoptosis in cytoplasm. Biochemical and biophysical research communications 8 21371439
2024 Stepwise phosphorylation and SUMOylation of PIDD1 drive PIDDosome assembly in response to DNA repair failure. Nature communications 7 39448602
2018 PIDD-dependent activation of caspase-2-mediated mitochondrial injury in E1A-induced cellular sensitivity to macrophage nitric oxide-induced apoptosis. Cell death discovery 6 30245858
2012 Janus-faced PIDD: a sensor for DNA damage-induced cell death or survival? Molecular cell 6 22980457
2006 PIDD: database for Protein Inter-atomic Distance Distributions. Nucleic acids research 5 17151078
2024 YTHDF2 promotes arsenic-induced malignant phenotypes by degrading PIDD1 mRNA in human keratinocytes. Chemico-biological interactions 4 39675544
2020 The expression and role of PIDD in retina after optic nerve crush. Journal of molecular histology 4 32065357
2016 Low expression of PIDD is associated with cell proliferation and apoptosis in hepatocellular carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 3 26846109
2023 Got PIDD1? Natural killer cells clear polyploid cells to ensure a balanced genome. The EMBO journal 2 37691515
2024 Noncanonical altPIDD1 protein: unveiling the true major translational output of the PIDD1 gene. Life science alliance 1 39532532
2023 Molecular basis of neurodevelopmental disorders caused by pathogenic variants of PIDD. Biochemical and biophysical research communications 1 36689811
2026 PARP4 ADP-ribosylates PIDD1 to complete a phospho/SUMO/PAR-ylation cascade that orchestrates PIDDosome assembly. Science advances 0 42054439
2019 E1A oncogene induced sensitization to NK cell induced apoptosis requires PIDD and Caspase-2. Cell death discovery 0 31285853

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