{"gene":"PIDD1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2000,"finding":"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.","method":"Reporter assay with p53 consensus element, antisense knockdown, overexpression in cells, ionizing radiation induction in p53+/+ vs p53-/- cells","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter assay, antisense KD, overexpression phenotype, genetic p53 dependence) in founding paper, replicated by subsequent studies","pmids":["10973264"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Cloning, co-immunoprecipitation, Western blot of processing fragments","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP study but domain architecture confirmed by multiple subsequent papers","pmids":["10825539"],"is_preprint":false},{"year":2005,"finding":"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.","method":"RAIDD-/- and caspase-2-/- MEFs, overexpression, caspase activity assays, cytochrome c release, subcellular fractionation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO of RAIDD and caspase-2 with multiple orthogonal phenotypic readouts, replicated by other labs","pmids":["16183742"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Co-immunoprecipitation, RNAi knockdown, NEMO sumoylation/ubiquitination assays, NF-κB reporter","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi knockdown, biochemical modification assays; replicated in subsequent studies","pmids":["16360037"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Site-directed mutagenesis of cleavage sites, Western blot of processing fragments, NF-κB reporter, caspase-2 activation assays, nuclear/cytoplasmic fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis of autoproteolytic sites with functional validation of both NF-κB and caspase-2 outcomes, replicated by subsequent work","pmids":["17159900"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Co-localization by fluorescence microscopy, co-immunoprecipitation of PIDD DD with nucleolin, overexpression assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and co-localization in single study; functional consequence of nucleolin interaction not fully established","pmids":["16982033"],"is_preprint":false},{"year":2007,"finding":"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.","method":"RT-PCR of isoforms, co-immunoprecipitation with RAIDD, NF-κB reporter, caspase-2 activation assays, overexpression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional reporter assays in single lab with two orthogonal approaches","pmids":["17637755"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Recombinant protein purification, gel filtration, multi-angle light scattering (MALS), X-ray crystallography (3.2 Å resolution)","journal":"Acta crystallographica Section F","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution and preliminary structural data from single study; functional validation not yet provided in this paper","pmids":["17329820"],"is_preprint":false},{"year":2008,"finding":"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.","method":"RNAi knockdown of PIDD, cytochrome c release assay, sub-G1 DNA content, nuclear fragmentation, inducible p53 expression system","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi epistasis with multiple apoptotic readouts in a single study","pmids":["18238895"],"is_preprint":false},{"year":2009,"finding":"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.","method":"PIDD knockout mouse generation, apoptosis assays (multiple stimuli), caspase-2 processing Western blot","journal":"Apoptosis","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple stress stimuli tested; negative finding is itself mechanistically informative and replicates across contexts","pmids":["19575295"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Co-immunoprecipitation, geldanamycin inhibition, Western blot of processing fragments, NF-κB reporter, caspase-2 activation, nuclear/cytoplasmic fractionation","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP with pharmacological inhibitor, fractionation, and two functional readouts (NF-κB and caspase-2) in one study with multiple orthogonal methods","pmids":["20966961"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Recombinant protein purification, dominant-negative mutagenesis, biochemical PIDDosome assembly assays","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with mutagenesis but single lab, limited functional validation","pmids":["20406701"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Proteomics screen, co-immunoprecipitation, PCNA ubiquitination assay, TLS assay, PIDD-deficient cells and mice, UV survival assay","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomics identification followed by biochemical validation, functional TLS assay in vitro and in vivo, multiple orthogonal methods","pmids":["21415862"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Phospho-specific antibody, site-directed mutagenesis of T788, Co-IP, caspase-2 activation assay, Chk1 inhibition, ATM kinase assay, genetic epistasis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — kinase assay, phospho-mutagenesis, Co-IP, functional caspase-2 activation, genetic epistasis; multiple orthogonal methods","pmids":["22854598"],"is_preprint":false},{"year":2012,"finding":"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.","method":"PIDD knockout MEFs and hematopoietic cells, NF-κB reporter, cytokine ELISA, γ-irradiation lymphoma model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple cell types, functional NF-κB and cytokine assays, in vivo tumor model","pmids":["23238565"],"is_preprint":false},{"year":2012,"finding":"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.","method":"PIDD-null and RAIDD-null neurons, caspase-2 activity assay, Co-IP of caspase-2/RAIDD complex, NGF deprivation and Aβ treatment","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO of both components, Co-IP, caspase activity assays; negative PIDD finding is mechanistically informative","pmids":["22515271"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Recombinant protein purification, solubilization assay, biochemical binding/pull-down, size-exclusion chromatography","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with purified proteins from single lab; functional consequence in cells not tested in this paper","pmids":["24064063"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Eμ-Myc/Raidd-/- and Pidd1-/- mice, tumor-free survival analysis, genetic epistasis","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic epistasis with defined tumor phenotype, single lab","pmids":["25857265"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, PIDD knockdown, DNA-PKcs recruitment to stalled forks (chromatin fractionation), ATR-Chk1 signaling assays, domain mapping","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP domain mapping, chromatin fractionation, ATR signaling assays, KD with multiple functional readouts in one study","pmids":["29309644"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation of PIDD-KEAP1, NRF2 ubiquitination assay, NRF2 stability assays, PIDD knockdown/overexpression with chemosensitivity assays, xenograft in vivo model","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ubiquitination assay, in vitro and in vivo functional assays with NRF2 dependence validated; multiple orthogonal methods","pmids":["31455821"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Genome-wide screen, Co-immunoprecipitation, fluorescence microscopy of PIDD1 at distal appendages, ANKRD26 knockdown/mutation, PIDDosome activation assay (caspase-2)","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen, Co-IP, direct localization by microscopy, functional caspase-2 readout, mutant validation; multiple orthogonal methods","pmids":["33350495"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, fluorescence co-localization, genome-edited PIDDosome reporter cell lines, exon trap for splice mutation","journal":"Translational psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, co-localization, genome-edited functional reporter in multiple families; mechanistic link between DD mutations and loss of CRADD interaction established","pmids":["33414379"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple centrosome amplification models, Co-IP of NEMO-PIDDosome, cytokine profiling, NK-cell functional assay; multiple orthogonal methods","pmids":["37530438"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro SUMOylation assay, mutagenesis of SUMO site, identification of E3 (PIAS1) and eraser (SENP3), structural basis (SIM in RAIDD), functional caspase-2 readout; multiple orthogonal methods in one study","pmids":["39448602"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, PIDDosome assembly assay, caspase-2 activation assay with mutant PIDD1 constructs","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional caspase-2 assay; single lab, consistent with parallel clinical genetics study","pmids":["36689811"],"is_preprint":false},{"year":2024,"finding":"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.","method":"m6A-RIP, RNA pulldown, YTHDF2 knockdown, Western blot of PIDD1 and PIDDosome components, caspase-2 activity assay, apoptosis assay","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA binding demonstrated by RIP, functional knockdown with multiple readouts; single lab","pmids":["39675544"],"is_preprint":false},{"year":2026,"finding":"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.","method":"ADP-ribosylation assays, PARP4/PARP14 manipulation, site-directed mutagenesis of E783, PIDD1 domain biochemistry, caspase-2 dimerization assay, ICL-induced apoptosis assay","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ADPr assay with identified enzyme (PARP4) and eraser (PARP14), mutagenesis, mechanistic ordering with SUMOylation, caspase dimerization assay, multiple orthogonal methods","pmids":["42054439"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mutagenesis with multiple functional readouts; preprint, not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"PIDD1 is a p53-transcriptional target and death-domain/LRR-containing scaffold protein that undergoes constitutive intein-like autoproteolysis (at S446→PIDD-C; S588→PIDD-CC) regulated by Hsp90; the resulting fragments differentially assemble two PIDDosome complexes—PIDD-C/RIP1/NEMO drives NF-κB activation (including in response to centrosome amplification via ANKRD26-mediated centriolar recruitment), while PIDD-CC/RAIDD/caspase-2 drives apoptosis; binding-partner selection at the PIDD death domain is controlled by a stepwise PTM cascade—ATM/ATR phosphorylation of T788 enables PIAS1-mediated SUMO-1 conjugation at K879 (countered by SENP3), which compartmentalizes PIDDosome assembly at nucleolar RAIDD, followed by PARP4-mediated ADP-ribosylation of E783 that is essential for caspase-2 dimerization and activation; additionally, PIDD1 promotes translesion synthesis by modulating p21-PCNA dissociation and PCNA monoubiquitination, recruits DNA-PKcs to stalled replication forks to facilitate ATR signaling, and stabilizes NRF2 by sequestering KEAP1."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2000,"claim":"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","pmids":["10973264"],"confidence":"High","gaps":["No molecular mechanism of how the protein executes apoptosis","Effector partners unidentified"]},{"year":2000,"claim":"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","pmids":["10825539"],"confidence":"Medium","gaps":["Functional consequence of FADD/MADD binding untested","Processing mechanism unknown"]},{"year":2005,"claim":"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","pmids":["16183742","16360037"],"confidence":"High","gaps":["What determines NF-κB vs apoptosis choice not resolved","Stoichiometry and assembly order undefined"]},{"year":2006,"claim":"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","pmids":["17159900","16982033"],"confidence":"High","gaps":["What regulates relative fragment abundance not established here","Functional role of nucleolin binding unclear"]},{"year":2010,"claim":"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","pmids":["20966961"],"confidence":"High","gaps":["How Hsp90 release is triggered upon PIDDosome formation unclear"]},{"year":2011,"claim":"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","pmids":["21415862"],"confidence":"High","gaps":["Whether this requires PIDDosome fragments not defined","Relation to caspase-2 arm unclear"]},{"year":2012,"claim":"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","pmids":["22854598"],"confidence":"High","gaps":["Additional PTMs downstream of T788 not yet known at this stage"]},{"year":2009,"claim":"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","pmids":["19575295"],"confidence":"High","gaps":["Reconciliation with prior overexpression apoptosis data incomplete","Tissue-specific roles untested here"]},{"year":2012,"claim":"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","pmids":["23238565","22515271"],"confidence":"High","gaps":["Mechanism of PIDD-independent RAIDD-caspase-2 activation in neurons unknown"]},{"year":2013,"claim":"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","pmids":["24064063","20406701"],"confidence":"Medium","gaps":["In-cell relevance of in vitro assembly order not tested","Single-lab reconstitution"]},{"year":2017,"claim":"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","pmids":["25857265"],"confidence":"Medium","gaps":["Molecular basis of RAIDD-independent tumor promotion unidentified"]},{"year":2019,"claim":"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","pmids":["29309644","31455821"],"confidence":"High","gaps":["Whether these depend on PIDD1 processing/PTMs unclear","Integration with PIDDosome arm undefined"]},{"year":2020,"claim":"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","pmids":["33350495"],"confidence":"High","gaps":["How extra centrioles are counted into a PIDD1 signal not fully resolved"]},{"year":2021,"claim":"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","pmids":["33414379","36689811"],"confidence":"High","gaps":["Neurodevelopmental mechanism downstream of lost PIDDosome unknown"]},{"year":2023,"claim":"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","pmids":["37530438"],"confidence":"High","gaps":["In vivo contribution to tumor immunosurveillance not fully established"]},{"year":2024,"claim":"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","pmids":["39448602"],"confidence":"High","gaps":["Why nucleolar compartmentalization is required mechanistically only partly resolved"]},{"year":2024,"claim":"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","pmids":["39675544"],"confidence":"Medium","gaps":["Single-lab, context-restricted to keratinocytes","Physiological breadth untested"]},{"year":2026,"claim":"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","pmids":["42054439"],"confidence":"High","gaps":["Structural mechanism of how E783-ADPr drives dimerization undefined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,3,2,16]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[19,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[5,23]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[20,22]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,4,26]},{"term_id":"R-HSA-162582","term_label":"Signal 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overexpression inhibits cell growth by inducing apoptosis, and antisense inhibition of PIDD attenuates p53-mediated apoptosis.\",\n      \"method\": \"Reporter assay with p53 consensus element, antisense knockdown, overexpression in cells, ionizing radiation induction in p53+/+ vs p53-/- cells\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter assay, antisense KD, overexpression phenotype, genetic p53 dependence) in founding paper, replicated by subsequent studies\",\n      \"pmids\": [\"10973264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Cloning, co-immunoprecipitation, Western blot of processing fragments\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP study but domain architecture confirmed by multiple subsequent papers\",\n      \"pmids\": [\"10825539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"RAIDD-/- and caspase-2-/- MEFs, overexpression, caspase activity assays, cytochrome c release, subcellular fractionation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO of RAIDD and caspase-2 with multiple orthogonal phenotypic readouts, replicated by other labs\",\n      \"pmids\": [\"16183742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, NEMO sumoylation/ubiquitination assays, NF-κB reporter\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi knockdown, biochemical modification assays; replicated in subsequent studies\",\n      \"pmids\": [\"16360037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis of cleavage sites, Western blot of processing fragments, NF-κB reporter, caspase-2 activation assays, nuclear/cytoplasmic fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis of autoproteolytic sites with functional validation of both NF-κB and caspase-2 outcomes, replicated by subsequent work\",\n      \"pmids\": [\"17159900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Co-localization by fluorescence microscopy, co-immunoprecipitation of PIDD DD with nucleolin, overexpression assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and co-localization in single study; functional consequence of nucleolin interaction not fully established\",\n      \"pmids\": [\"16982033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR of isoforms, co-immunoprecipitation with RAIDD, NF-κB reporter, caspase-2 activation assays, overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional reporter assays in single lab with two orthogonal approaches\",\n      \"pmids\": [\"17637755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant protein purification, gel filtration, multi-angle light scattering (MALS), X-ray crystallography (3.2 Å resolution)\",\n      \"journal\": \"Acta crystallographica Section F\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution and preliminary structural data from single study; functional validation not yet provided in this paper\",\n      \"pmids\": [\"17329820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown of PIDD, cytochrome c release assay, sub-G1 DNA content, nuclear fragmentation, inducible p53 expression system\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi epistasis with multiple apoptotic readouts in a single study\",\n      \"pmids\": [\"18238895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"PIDD knockout mouse generation, apoptosis assays (multiple stimuli), caspase-2 processing Western blot\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple stress stimuli tested; negative finding is itself mechanistically informative and replicates across contexts\",\n      \"pmids\": [\"19575295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, geldanamycin inhibition, Western blot of processing fragments, NF-κB reporter, caspase-2 activation, nuclear/cytoplasmic fractionation\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP with pharmacological inhibitor, fractionation, and two functional readouts (NF-κB and caspase-2) in one study with multiple orthogonal methods\",\n      \"pmids\": [\"20966961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant protein purification, dominant-negative mutagenesis, biochemical PIDDosome assembly assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with mutagenesis but single lab, limited functional validation\",\n      \"pmids\": [\"20406701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomics screen, co-immunoprecipitation, PCNA ubiquitination assay, TLS assay, PIDD-deficient cells and mice, UV survival assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomics identification followed by biochemical validation, functional TLS assay in vitro and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"21415862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Phospho-specific antibody, site-directed mutagenesis of T788, Co-IP, caspase-2 activation assay, Chk1 inhibition, ATM kinase assay, genetic epistasis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — kinase assay, phospho-mutagenesis, Co-IP, functional caspase-2 activation, genetic epistasis; multiple orthogonal methods\",\n      \"pmids\": [\"22854598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"PIDD knockout MEFs and hematopoietic cells, NF-κB reporter, cytokine ELISA, γ-irradiation lymphoma model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple cell types, functional NF-κB and cytokine assays, in vivo tumor model\",\n      \"pmids\": [\"23238565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"PIDD-null and RAIDD-null neurons, caspase-2 activity assay, Co-IP of caspase-2/RAIDD complex, NGF deprivation and Aβ treatment\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO of both components, Co-IP, caspase activity assays; negative PIDD finding is mechanistically informative\",\n      \"pmids\": [\"22515271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant protein purification, solubilization assay, biochemical binding/pull-down, size-exclusion chromatography\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with purified proteins from single lab; functional consequence in cells not tested in this paper\",\n      \"pmids\": [\"24064063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Eμ-Myc/Raidd-/- and Pidd1-/- mice, tumor-free survival analysis, genetic epistasis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic epistasis with defined tumor phenotype, single lab\",\n      \"pmids\": [\"25857265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, PIDD knockdown, DNA-PKcs recruitment to stalled forks (chromatin fractionation), ATR-Chk1 signaling assays, domain mapping\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP domain mapping, chromatin fractionation, ATR signaling assays, KD with multiple functional readouts in one study\",\n      \"pmids\": [\"29309644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of PIDD-KEAP1, NRF2 ubiquitination assay, NRF2 stability assays, PIDD knockdown/overexpression with chemosensitivity assays, xenograft in vivo model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ubiquitination assay, in vitro and in vivo functional assays with NRF2 dependence validated; multiple orthogonal methods\",\n      \"pmids\": [\"31455821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-wide screen, Co-immunoprecipitation, fluorescence microscopy of PIDD1 at distal appendages, ANKRD26 knockdown/mutation, PIDDosome activation assay (caspase-2)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen, Co-IP, direct localization by microscopy, functional caspase-2 readout, mutant validation; multiple orthogonal methods\",\n      \"pmids\": [\"33350495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence co-localization, genome-edited PIDDosome reporter cell lines, exon trap for splice mutation\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, co-localization, genome-edited functional reporter in multiple families; mechanistic link between DD mutations and loss of CRADD interaction established\",\n      \"pmids\": [\"33414379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple centrosome amplification models, Co-IP of NEMO-PIDDosome, cytokine profiling, NK-cell functional assay; multiple orthogonal methods\",\n      \"pmids\": [\"37530438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro SUMOylation assay, mutagenesis of SUMO site, identification of E3 (PIAS1) and eraser (SENP3), structural basis (SIM in RAIDD), functional caspase-2 readout; multiple orthogonal methods in one study\",\n      \"pmids\": [\"39448602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, PIDDosome assembly assay, caspase-2 activation assay with mutant PIDD1 constructs\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional caspase-2 assay; single lab, consistent with parallel clinical genetics study\",\n      \"pmids\": [\"36689811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"m6A-RIP, RNA pulldown, YTHDF2 knockdown, Western blot of PIDD1 and PIDDosome components, caspase-2 activity assay, apoptosis assay\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA binding demonstrated by RIP, functional knockdown with multiple readouts; single lab\",\n      \"pmids\": [\"39675544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"ADP-ribosylation assays, PARP4/PARP14 manipulation, site-directed mutagenesis of E783, PIDD1 domain biochemistry, caspase-2 dimerization assay, ICL-induced apoptosis assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ADPr assay with identified enzyme (PARP4) and eraser (PARP14), mutagenesis, mechanistic ordering with SUMOylation, caspase dimerization assay, multiple orthogonal methods\",\n      \"pmids\": [\"42054439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mutagenesis with multiple functional readouts; preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PIDD1 is a p53-transcriptional target and death-domain/LRR-containing scaffold protein that undergoes constitutive intein-like autoproteolysis (at S446→PIDD-C; S588→PIDD-CC) regulated by Hsp90; the resulting fragments differentially assemble two PIDDosome complexes—PIDD-C/RIP1/NEMO drives NF-κB activation (including in response to centrosome amplification via ANKRD26-mediated centriolar recruitment), while PIDD-CC/RAIDD/caspase-2 drives apoptosis; binding-partner selection at the PIDD death domain is controlled by a stepwise PTM cascade—ATM/ATR phosphorylation of T788 enables PIAS1-mediated SUMO-1 conjugation at K879 (countered by SENP3), which compartmentalizes PIDDosome assembly at nucleolar RAIDD, followed by PARP4-mediated ADP-ribosylation of E783 that is essential for caspase-2 dimerization and activation; additionally, PIDD1 promotes translesion synthesis by modulating p21-PCNA dissociation and PCNA monoubiquitination, recruits DNA-PKcs to stalled replication forks to facilitate ATR signaling, and stabilizes NRF2 by sequestering KEAP1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #4]. 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-\\u03baB activation and PIDD-CC engaging the adaptor RAIDD to activate caspase-2 [#4, #10, #3, #2]. 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 [#13, #23, #26]. 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-\\u03baB-driven sterile inflammation, and control of hepatocyte/cardiomyocyte ploidy [#20, #22]. Beyond cell death, PIDD1 promotes translesion synthesis by modulating p21\\u2013PCNA dissociation and PCNA monoubiquitination, recruits DNA-PKcs to stalled forks to enable ATR signaling, and stabilizes NRF2 by sequestering KEAP1 to drive chemoresistance [#12, #18, #19]. Biallelic death-domain mutations that abolish PIDD1\\u2013RAIDD/CRADD interaction and PIDDosome function cause human intellectual disability [#21].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established PIDD1 as a transcriptional effector of p53 in DNA-damage-induced apoptosis, placing it downstream of the central tumor suppressor.\",\n      \"evidence\": \"p53 consensus reporter assay, antisense knockdown, and IR induction in p53+/+ vs p53-/- cells\",\n      \"pmids\": [\"10973264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No molecular mechanism of how the protein executes apoptosis\", \"Effector partners unidentified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the LRR\\u2013death-domain architecture and showed the protein is proteolytically processed and engages death-domain partners, hinting at a scaffolding role.\",\n      \"evidence\": \"Cloning, Co-IP with FADD and MADD, Western blot of processing fragments\",\n      \"pmids\": [\"10825539\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of FADD/MADD binding untested\", \"Processing mechanism unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified RAIDD and caspase-2 as the essential downstream apoptotic module and revealed a parallel nuclear RIP1/NEMO complex driving NF-\\u03baB, establishing PIDD1 as a bifurcating stress hub.\",\n      \"evidence\": \"RAIDD-/- and caspase-2-/- MEFs, reciprocal Co-IP, RNAi, NEMO modification and NF-\\u03baB reporter assays\",\n      \"pmids\": [\"16183742\", \"16360037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What determines NF-\\u03baB vs apoptosis choice not resolved\", \"Stoichiometry and assembly order undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed autoproteolysis at S446 and S588 generates PIDD-C and PIDD-CC fragments whose differential generation dictates NF-\\u03baB versus caspase-2 output, providing the molecular basis for output switching.\",\n      \"evidence\": \"Active-site mutagenesis of cleavage sites, fragment Western blots, NF-\\u03baB/caspase-2 readouts, fractionation; plus nucleolar/nucleolin colocalization\",\n      \"pmids\": [\"17159900\", \"16982033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What regulates relative fragment abundance not established here\", \"Functional role of nucleolin binding unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified Hsp90/p23 as the chaperone required for PIDD1 maturation, defining an upstream checkpoint that gates both downstream arms.\",\n      \"evidence\": \"Co-IP, geldanamycin inhibition, fragment Western blot, NF-\\u03baB and caspase-2 assays, fractionation\",\n      \"pmids\": [\"20966961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Hsp90 release is triggered upon PIDDosome formation unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a non-apoptotic genome-maintenance function: PIDD1 binds PCNA to promote translesion synthesis via p21-PCNA dissociation and PCNA monoubiquitination.\",\n      \"evidence\": \"Proteomics, Co-IP, PCNA ubiquitination and TLS assays, PIDD-deficient cells and mice, UV survival\",\n      \"pmids\": [\"21415862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this requires PIDDosome fragments not defined\", \"Relation to caspase-2 arm unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed ATM phosphorylation of T788 within the death domain is the switch that licenses RAIDD binding/caspase-2 activation versus default RIP1/NF-\\u03baB engagement, mechanistically linking damage sensing to fate choice.\",\n      \"evidence\": \"Phospho-specific antibody, T788 mutagenesis, ATM kinase assay, Co-IP, caspase-2 and Chk1-suppressed pathway epistasis\",\n      \"pmids\": [\"22854598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Additional PTMs downstream of T788 not yet known at this stage\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic knockout showed PIDD1 is dispensable for canonical DNA-damage and death-receptor apoptosis in vivo, narrowing its essential role to NF-\\u03baB and context-specific functions.\",\n      \"evidence\": \"PIDD knockout mice, multi-stimulus apoptosis assays, caspase-2 processing Western blot\",\n      \"pmids\": [\"19575295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with prior overexpression apoptosis data incomplete\", \"Tissue-specific roles untested here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined PIDD1 as rate-limiting for DNA-damage-induced NF-\\u03baB/cytokine signaling and dispensable for survival, and showed neuronal caspase-2 death uses RAIDD independently of PIDD1, sharpening which contexts require the scaffold.\",\n      \"evidence\": \"PIDD knockout cells, NF-\\u03baB reporter, cytokine ELISA, lymphoma model; PIDD/RAIDD-null neurons with caspase-2 assays\",\n      \"pmids\": [\"23238565\", \"22515271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of PIDD-independent RAIDD-caspase-2 activation in neurons unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Reconstituted the ordered PIDDosome assembly hierarchy (PIDD DD \\u2192 RAIDD \\u2192 caspase-2 CARD), explaining how the scaffold organizes the apoptotic platform.\",\n      \"evidence\": \"Recombinant proteins, solubilization and pull-down assays, gel filtration, dominant-negative mutants\",\n      \"pmids\": [\"24064063\", \"20406701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In-cell relevance of in vitro assembly order not tested\", \"Single-lab reconstitution\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed Pidd1 promotes E\\u03bc-Myc lymphomagenesis independently of RAIDD/PIDDosome, demonstrating a tumor-promoting function uncoupled from caspase-2 death.\",\n      \"evidence\": \"E\\u03bc-Myc/Raidd-/- and Pidd1-/- mice, tumor-free survival, genetic epistasis\",\n      \"pmids\": [\"25857265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of RAIDD-independent tumor promotion unidentified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP and domain mapping, chromatin fractionation, ATR-Chk1 assays; KEAP1 Co-IP, NRF2 ubiquitination/stability, xenograft\",\n      \"pmids\": [\"29309644\", \"31455821\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these depend on PIDD1 processing/PTMs unclear\", \"Integration with PIDDosome arm undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified ANKRD26 as the centriolar receptor that recruits PIDD1 to distal appendages, defining the structural basis for centrosome-amplification sensing by the PIDDosome.\",\n      \"evidence\": \"Genome-wide screen, Co-IP, microscopy of PIDD1 at distal appendages, ANKRD26 knockdown/mutation, caspase-2 readout\",\n      \"pmids\": [\"33350495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How extra centrioles are counted into a PIDD1 signal not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked PIDD1 death-domain mutations that abolish RAIDD/CRADD binding and PIDDosome function to human intellectual disability, establishing physiological importance of the apoptotic scaffold.\",\n      \"evidence\": \"Co-IP, co-localization, genome-edited PIDDosome reporter lines, patient family genetics\",\n      \"pmids\": [\"33414379\", \"36689811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neurodevelopmental mechanism downstream of lost PIDDosome unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed centrosome amplification triggers a NEMO-PIDDosome NF-\\u03baB program producing sterile inflammation and immune surveillance, broadening PIDD1's role from cell-intrinsic to paracrine.\",\n      \"evidence\": \"Centrosome amplification models, NEMO-PIDDosome Co-IP, cytokine profiling, macrophage polarization and NK-killing assays, ANKRD26 knockdown\",\n      \"pmids\": [\"37530438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution to tumor immunosurveillance not fully established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"SUMOylation assays, K879 mutagenesis, ATR kinase assays, PIAS1/SENP3 manipulation, nucleolar fractionation, ICL apoptosis assay\",\n      \"pmids\": [\"39448602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why nucleolar compartmentalization is required mechanistically only partly resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified m6A/YTHDF2-mediated decay of PIDD1 mRNA as a post-transcriptional brake on PIDDosome-driven apoptosis in arsenic-exposed cells.\",\n      \"evidence\": \"m6A-RIP, RNA pulldown, YTHDF2 knockdown, PIDDosome Western blots, caspase-2 and apoptosis assays\",\n      \"pmids\": [\"39675544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab, context-restricted to keratinocytes\", \"Physiological breadth untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro ADPr assays, PARP4/PARP14 manipulation, E783 mutagenesis, caspase-2 dimerization and ICL apoptosis assays\",\n      \"pmids\": [\"42054439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of how E783-ADPr drives dimerization undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PIDD1's apoptotic scaffolding, NF-\\u03baB 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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 3, 2, 16]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [19, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [5, 23]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [20, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 4, 26]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 14, 22]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [12, 18, 23]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [13, 19]}\n    ],\n    \"complexes\": [\"PIDDosome (PIDD1/RAIDD/caspase-2)\", \"NEMO-PIDDosome (PIDD1/RIPK1/NEMO)\"],\n    \"partners\": [\"CRADD\", \"RIPK1\", \"IKBKG\", \"ANKRD26\", \"PCNA\", \"PRKDC\", \"KEAP1\", \"HSP90\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}