{"gene":"PELI1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2009,"finding":"Peli1 (E3 ubiquitin ligase) binds to and ubiquitinates RIP1, mediating K63-linked ubiquitination to promote IKK activation downstream of the TLR3/TLR4 adaptor TRIF, but is dispensable for IKK-NF-κB activation by MyD88-dependent TLRs and IL-1R.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, genetic knockout mice, cytokine induction assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding and ubiquitination assays with genetic KO validation, replicated in multiple TLR contexts","pmids":["19734906"],"is_preprint":false},{"year":2011,"finding":"Peli1 mediates K48-linked ubiquitination of c-Rel (NF-κB family member), targeting it for degradation; Peli1 deficiency causes nuclear accumulation of c-Rel and hyperactivation of T cells, leading to spontaneous autoimmunity.","method":"Genetic knockout mice, ubiquitination assays, nuclear fractionation/immunoblot, T cell activation assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — K48 ubiquitination of c-Rel established with ubiquitination assays and nuclear accumulation confirmed by fractionation in KO cells, supported by in vivo autoimmunity phenotype","pmids":["21874024"],"is_preprint":false},{"year":2013,"finding":"Peli1 promotes degradation of TRAF3 (a potent inhibitor of MAPK activation) in microglia via ubiquitin-mediated proteolysis, thereby enabling TLR pathway-driven chemokine and cytokine induction; ablation of TRAF3 restores microglial activation in Peli1-deficient mice.","method":"Genetic knockout mice, EAE model, TRAF3 protein level analysis, epistasis rescue experiment (Traf3 ablation in Peli1-KO)","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis rescue (Traf3-/- restores phenotype in Peli1-KO) plus protein degradation assays in primary microglia","pmids":["23603814"],"is_preprint":false},{"year":2017,"finding":"PELI1 mediates K63-linked ubiquitination of RIPK1 at lysine 115 in a kinase-activity-dependent manner during necroptosis, promoting necrosome formation (RIPK1-RIPK3 interaction) and RIPK3/MLKL activation; separately, PELI1 maintains c-FLIP mRNA levels, and its deficiency sensitizes cells to apoptosis.","method":"Ubiquitination assays with site-directed mutagenesis (K115), co-immunoprecipitation of RIPK1-RIPK3, RIPK1 kinase inhibitor experiments, knockout cell lines and mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-specific mutagenesis (K115), kinase-dependent ubiquitination, and necrosome assembly assays with multiple orthogonal methods","pmids":["29078411"],"is_preprint":false},{"year":2018,"finding":"PELI1 selectively targets kinase-active RIP3 (phosphorylated on T182) for K48-linked polyubiquitylation at K363 via interaction with the PELI1 FHA domain, leading to proteasome-dependent RIP3 degradation and prevention of necroptosis triggered by RIP3 hyperactivation.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, site-directed mutagenesis (T182, K363), proteasome inhibitor experiments, patient TEN keratinocyte samples","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro ubiquitination with phospho-mimetic and K363 mutants, FHA domain interaction mapped, replicated by companion paper (PMID:30269743)","pmids":["29883609","30269743"],"is_preprint":false},{"year":2018,"finding":"Peli1 functions as an E3 ligase for NF-κB-inducing kinase (NIK), mediating K48-linked ubiquitination and proteasomal degradation of NIK, thereby suppressing noncanonical NF-κB signaling in B cells and restraining autoantibody production in lupus-like disease.","method":"Co-immunoprecipitation, ubiquitination assays, B cell-specific conditional knockout mice, lupus disease model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct ubiquitination of NIK shown with K48 linkage, genetic rescue in B cell-specific KO with noncanonical NF-κB readouts","pmids":["29555915"],"is_preprint":false},{"year":2018,"finding":"Peli1 binds Mdmx in vitro and in vivo and promotes non-degradative ubiquitination of Mdmx, causing its cytoplasmic localization; Peli1 loss or knockdown induces nuclear localization of Mdmx and suppresses p53 activity, and Peli1-null mice show accelerated Myc-induced tumorigenesis associated with reduced p53 function.","method":"Co-immunoprecipitation, in vitro binding assay, ubiquitination assay, subcellular fractionation, Peli1-knockout mice with Myc-driven tumor model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct in vitro binding and ubiquitination plus subcellular fractionation with functional p53 readout in KO mice, single lab but multiple orthogonal methods","pmids":["29523541"],"is_preprint":false},{"year":2019,"finding":"Peli1 FHA domain binds to phosphorylated HPD (T382 phosphorylated by STK33) and mediates polyubiquitylation and degradation of HPD; TTC36 competes with STK33 to reduce HPD phosphorylation and thus prevents Peli1 recruitment and HPD degradation.","method":"Co-immunoprecipitation, in vitro kinase assay, ubiquitination assay, Ttc36 knockout mice with tyrosinemia phenotype","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — FHA domain-phospho interaction mapped, in vitro ubiquitination confirmed, in vivo genetic model with metabolic phenotype","pmids":["31537781"],"is_preprint":false},{"year":2019,"finding":"Peli1 Ring domain directly binds Hsp90, and this interaction enhances IRE1α phosphorylation in cardiac microvascular endothelial cells, promoting ER stress and microvascular injury; Peli1 deficiency in endothelial cells alleviates diabetes-induced cardiac microvascular permeability.","method":"Co-immunoprecipitation (Ring domain-Hsp90), endothelial cell-specific Peli1 knockout, IRE1α phosphorylation assays, permeability assays in diabetic mouse model","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — domain-level Co-IP and functional KO, but mechanistic link between Hsp90 binding and IRE1α activation not fully reconstituted","pmids":["31260751"],"is_preprint":false},{"year":2020,"finding":"Peli1 mediates non-degradative ubiquitination of TSC1, promoting TSC1-TSC2 dimerization and TSC2 stabilization, thereby inhibiting mTORC1 activity; Peli1 ablation in T cells markedly increases glycolysis via mTORC1 activation and enhances antitumor immunity.","method":"Ubiquitination assays, Co-immunoprecipitation of TSC1-TSC2, mTORC1 activity assays, Peli1-knockout T cells, tumor models","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ubiquitination of TSC1 mapped, TSC1-TSC2 dimerization confirmed by Co-IP, mTORC1 functional readout in KO T cells with multiple orthogonal methods","pmids":["33215753"],"is_preprint":false},{"year":2020,"finding":"Peli1 directly ubiquitinates C/EBPβ (a transcription factor for scavenger receptor CD36), promoting its degradation; Peli1 loss increases C/EBPβ protein levels and CD36 expression, enhancing microglial Aβ phagocytosis and reducing Aβ deposition in 5×FAD mice.","method":"Co-immunoprecipitation, ubiquitination assay, Peli1-knockout microglia, 5×FAD mouse model, phagocytosis assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct E3-substrate ubiquitination shown, C/EBPβ-CD36 axis confirmed, in vivo Aβ deposition phenotype in KO model","pmids":["33017390"],"is_preprint":false},{"year":2021,"finding":"Peli1 conjugates K63-linked ubiquitin chains onto lysine 55 of ASC (inflammasome adaptor), facilitating ASC/NLRP3 interaction and ASC oligomerization, thereby promoting NLRP3 inflammasome activation and IL-1β maturation; this is specific to NLRP3 (not Aim2, NLRP1, or NLRC4 inflammasomes).","method":"Ubiquitination assays with site-directed mutagenesis (K55 of ASC), co-immunoprecipitation (ASC-NLRP3), ASC oligomerization assays, Peli1-knockout mice with peritonitis/LPS shock models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — K55 site-specific ubiquitination with mutagenesis, ASC-NLRP3 interaction and oligomerization measured, in vivo KO with multiple inflammasome inducers tested","pmids":["34706239"],"is_preprint":false},{"year":2021,"finding":"Peli1 deficiency promotes c-Rel-mediated inducible T-cell costimulator (ICOS) expression; increased ICOS activates PI3K-AKT signaling, suppressing Klf2 expression to promote T follicular helper (Tfh) cell differentiation; reconstitution of Klf2 abolishes the Tfh differentiation difference between WT and Peli1-KO cells.","method":"Bone marrow chimeric experiments, flow cytometry, PI3K-AKT signaling assays, Klf2 reconstitution rescue experiments, Peli1-KO mice","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis rescue (Klf2 reconstitution) established pathway position; ICOS upregulation mechanistically linked to c-Rel, but direct ubiquitination of ICOS not shown","pmids":["33707688"],"is_preprint":false},{"year":2021,"finding":"PELI1 mediates K48-linked polyubiquitination and proteasomal degradation of NF-κB-inducing kinase (NIK), thereby inhibiting noncanonical NF-κB pathway activation and reducing Bclxl expression, which sensitizes esophageal squamous cancer cells to ionizing radiation-induced apoptosis.","method":"Ubiquitination assays, NIK protein stability assays, noncanonical NF-κB reporter assays, PELI1 KD/KO in cancer cells, in vivo tumor irradiation model","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — K48 ubiquitination of NIK shown, pathway consequence (Bclxl/apoptosis) measured, single lab with multiple methods","pmids":["34738714"],"is_preprint":false},{"year":2022,"finding":"Peli1 (via its Ring domain) directly interacts with P62/sequestosome-1 and promotes K63-linked ubiquitination of P62 at K7, inhibiting P62 dimerization and autophagic degradation, thereby impairing autophagy flux during myocardial ischemia/reperfusion injury.","method":"Co-immunoprecipitation, GST-pulldown, in vitro ubiquitination with site mutagenesis (K7), LC3/P62 flux assays, Peli1-KO mice with I/R model","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — GST-pulldown plus Co-IP map domain interaction, K7 mutagenesis establishes site, autophagy flux assay with KO in vivo","pmids":["36179399"],"is_preprint":false},{"year":2023,"finding":"Peli1 promotes K63-linked ubiquitination and nuclear translocation of IRF5 in macrophages, driving M1 polarization; Peli1 deficiency in macrophages reduces IRF5 nuclear translocation, suppresses M1 polarization, and alleviates myocardial ischemia/reperfusion injury.","method":"Ubiquitination assays, nuclear fractionation for IRF5, macrophage-specific Peli1 conditional knockout, I/R mouse model, flow cytometry for M1/M2 markers","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — K63 ubiquitination of IRF5 and nuclear translocation shown, in vivo macrophage-specific KO with disease model, single lab","pmids":["36822176"],"is_preprint":false},{"year":2024,"finding":"Peli1 binds HNF4α via its RING-like domain and promotes HNF4α ubiquitination at residues K307 and K309, leading to HNF4α degradation, reduced fatty acid oxidation gene expression, and exacerbated cardiac hypertrophy; HNF4α inhibition abolishes the cardioprotective effect of Peli1 knockout.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay with K307/K309 mutagenesis, RNA-seq, FAO stress assay, rAAV9-HNF4α delivery, Peli1 KO mice with TAC model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mass spectrometry identified ubiquitination sites confirmed by mutagenesis, domain interaction mapped by Co-IP, in vivo rescue with AAV-HNF4α","pmids":["38346961"],"is_preprint":false},{"year":2024,"finding":"Peli1 facilitates ubiquitination and proteasomal degradation of Foxp1 in macrophages, relieving Foxp1-mediated transcriptional inhibition of IL-6, thus promoting macrophage activation and IL-6-driven pulmonary vascular remodeling; myeloid Foxp1 deficiency partially eliminates the protective effect of myeloid Peli1 deficiency in pulmonary hypertension.","method":"Proteomic analysis, co-immunoprecipitation, Foxp1 stability assays, myeloid-specific Peli1-KO and Foxp1-KO mice, hypoxia-induced PH model, IL-6 transcription assays","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (Foxp1 KO partially reverses Peli1 KO protection), ubiquitination/degradation of Foxp1 shown, single lab","pmids":["39618410"],"is_preprint":false},{"year":2024,"finding":"PELI1 interacts with Ribosomal Protein S3 (RPS3) through its FHA domain and promotes K48-linked polyubiquitination and degradation of RPS3, which activates the PI3K/Akt/GSK3β signaling pathway and reduces RPS3-mediated protection of p53 from MDM2-dependent degradation, thereby promoting pancreatic cancer progression.","method":"Co-immunoprecipitation, GST-pulldown, ubiquitination assays, immunofluorescence co-localization, in vivo xenograft and liver metastasis models","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — FHA domain-RPS3 interaction mapped by GST-pulldown and Co-IP, K48 ubiquitination demonstrated, downstream signaling pathway confirmed, single lab","pmids":["38528516"],"is_preprint":false},{"year":2024,"finding":"PELI1 mediates K63-linked ubiquitination and degradation of IRAK2 in airway epithelial cells; IRAK2 overexpression reverses the anti-inflammatory effect of PELI1 overexpression by activating p38-MAPK/NF-κB signaling.","method":"CRISPR/Cas9 KO, AAV6.2 overexpression in vivo, ubiquitination assays, epistasis rescue (IRAK2 re-expression), MAPK/NF-κB signaling assays","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — K63 ubiquitination of IRAK2 shown, genetic rescue confirms pathway epistasis, single lab","pmids":["40986758"],"is_preprint":false},{"year":2023,"finding":"Peli1 promotes miR-494-3p expression via NF-κB/AP-1 transcriptional activation in cardiomyocytes under mechanical stretch; cardiomyocyte-derived exosomes enriched with miR-494-3p activate cardiac fibroblasts by targeting PTEN, amplifying AKT, SMAD2/3, and ERK phosphorylation, thereby contributing to cardiac fibrosis.","method":"CM-conditional Peli1 knockout mice, miRNA microarray, exosome isolation, NF-κB/AP-1 reporter assays, PTEN/AKT pathway assays in cardiac fibroblasts","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Peli1 conditional KO with exosome fractionation and miRNA array, NF-κB/AP-1 link to miR-494-3p shown, single lab","pmids":["36520055"],"is_preprint":false},{"year":2025,"finding":"PELI1 mediates K48-linked ubiquitination and degradation of YB-1 in macrophages, preventing NLRP3 inflammasome activation; YTHDC2-recognized m6A modification of Peli1 mRNA (mediated by METTL3) promotes Peli1 mRNA degradation, reducing Peli1 protein levels during atherosclerosis.","method":"Ubiquitination assays, YB-1 stability assays, m6A methylation assay, YTHDC2 co-precipitation, in vivo atherosclerosis model with rescue experiments","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ubiquitination of YB-1 and m6A regulation of Peli1 mRNA both demonstrated, single lab, rescue experiments included","pmids":["40102597"],"is_preprint":false},{"year":2023,"finding":"PELI1 interacts with EGFR; EGFR activation phosphorylates PELI1 at Tyr154 and Thr264, activating its E3 ubiquitin ligase activity; reciprocally, PELI1 promotes K63-linked polyubiquitination of EGFR to enhance EGFR stability, creating a positive feedback loop that promotes breast cancer metastasis.","method":"Co-immunoprecipitation, phospho-site mapping, ubiquitination assays, K63-linkage specific assays, breast cancer cell migration/invasion assays, in vivo metastasis model","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal regulation (EGFR phosphorylates PELI1; PELI1 ubiquitinates EGFR) shown by Co-IP and ubiquitination assays, single lab","pmids":["36841821"],"is_preprint":false},{"year":2024,"finding":"PELI1 interacts with INPP5J via Co-immunoprecipitation and promotes ubiquitination and proteasomal degradation of INPP5J in pancreatic cancer cells; INPP5J overexpression reverses the pro-tumorigenic effects of PELI1 overexpression.","method":"Co-immunoprecipitation, ubiquitination assays, gain/loss-of-function experiments, xenograft model, epistasis rescue with INPP5J overexpression","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and ubiquitination shown, epistasis confirmed by rescue, single lab","pmids":["38685520"],"is_preprint":false},{"year":2025,"finding":"Peli1 is identified as a key regulator of microglial exosome release; Peli1 inhibition reduces microglial activation and the generation of proinflammatory exosomes that drive neurotoxic astrocyte conversion; a feedback loop was identified where neurotoxic astrocytes upregulate Peli1 expression in microglia.","method":"PLX3397 microglial depletion, GW4869 exosome secretion blockade, purified exosome injection in vivo, Peli1 inhibition in microglia, astrocyte phenotype assays","journal":"Pharmacological research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — exosome functional data is strong but direct mechanism by which Peli1 controls exosome release is not biochemically characterized; single lab","pmids":["40816423"],"is_preprint":false},{"year":2015,"finding":"Peli1 negatively regulates type I interferon (IFN-β) induction in microglia in response to TLR ligands and vesicular stomatitis virus; Peli1-deficient mice show heightened CNS IFN-I responses and reduced brain viral titers after intranasal VSV infection.","method":"Peli1 genetic knockout mice, intranasal VSV infection, IFN-β measurement in microglia in vitro and CNS in vivo, viral titer assay","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic KO with defined IFN-I readout in primary microglia and in vivo, but molecular mechanism not resolved beyond E3 ligase activity, single lab","pmids":["26131354"],"is_preprint":false},{"year":2026,"finding":"PELI1 promotes ubiquitination and degradation of FTH1 (ferritin heavy chain) in ovarian granulosa cells, contributing to ferroptosis; the P53/PELI1/FTH1 pathway is activated by hyperandrogenism in PCOS, and iron death inhibitor deferoxamine alleviates follicular development disorders.","method":"Transcriptome sequencing, cellular ubiquitination assays, PCOS mouse model, iron death inhibitor rescue experiments","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ubiquitination of FTH1 inferred from transcriptomic and cellular data, mechanistic chain not fully reconstituted, single lab","pmids":["41620040"],"is_preprint":false},{"year":2024,"finding":"PELI1 interacts with TCF-1 and promotes its ubiquitination and degradation; inhibition of TCF-1 reduces the effects of PELI1 knockdown on CD4+ T cell differentiation toward Th2 and Treg cells, placing PELI1 upstream of TCF-1 in T cell lineage decisions.","method":"Co-immunoprecipitation, ubiquitination assays, TCF-1 rescue experiments, flow cytometry for T cell subsets","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination of TCF-1 shown with rescue, but ubiquitination site and chain type not mapped, single lab","pmids":["39617092"],"is_preprint":false}],"current_model":"PELI1 is a RING-like domain E3 ubiquitin ligase that uses its FHA domain to recognize phosphorylated substrates and its RING domain to catalyze substrate ubiquitination with multiple linkage types and functional outcomes: it mediates K63-linked ubiquitination of RIP1 (promoting TRIF-dependent NF-κB activation), K63-linked ubiquitination of RIPK1-K115 (promoting necrosome formation and necroptosis), K48-linked ubiquitination of kinase-active RIP3-K363 (targeting it for proteasomal degradation), K48-linked ubiquitination of c-Rel (limiting T cell activation), K48-linked ubiquitination of NIK (suppressing noncanonical NF-κB), K48-linked ubiquitination of TRAF3 (enabling MAPK activation in microglia), non-degradative ubiquitination of TSC1 (inhibiting mTORC1 and T cell glycolysis), K63-linked ubiquitination of ASC-K55 (promoting NLRP3 inflammasome assembly), K63-linked ubiquitination of IRF5 (driving macrophage M1 polarization), and K48-linked ubiquitination of substrates including C/EBPβ, HNF4α, Mdmx, HPD, Foxp1, P62, YB-1, IRAK2, RPS3, INPP5J, and FTH1, collectively placing PELI1 as a pleiotropic ubiquitin ligase at the intersection of TLR/innate immunity, NF-κB signaling, cell death regulation, metabolic reprogramming, and tissue homeostasis."},"narrative":{"mechanistic_narrative":"PELI1 is a RING-like domain E3 ubiquitin ligase that operates at the intersection of TLR/innate immunity, NF-κB signaling, cell death, and metabolic control, using its FHA domain to read phosphorylated substrates and its RING domain to catalyze ubiquitin transfer with linkage-specific outcomes [PMID:19734906, PMID:29883609, PMID:30269743]. In TLR signaling it conjugates K63-linked chains onto RIP1 to drive TRIF-dependent IKK–NF-κB activation [PMID:19734906], while shaping inflammation through degradative ubiquitination of inhibitory factors—K48-linked degradation of c-Rel to restrain T cell activation and prevent autoimmunity [PMID:21874024], TRAF3 degradation to license MAPK-driven microglial activation [PMID:23603814], and K48-linked degradation of NIK to suppress noncanonical NF-κB in B cells [PMID:29555915]. PELI1 is a bidirectional rheostat of programmed cell death: it promotes necroptosis by K63-linked ubiquitination of RIPK1 at K115 to nucleate the RIPK1–RIPK3 necrosome [PMID:29078411], yet limits it by selectively K48-ubiquitinating kinase-active RIP3 at K363 for proteasomal degradation [PMID:29883609, PMID:30269743]. Beyond cell death, it controls metabolism and growth signaling through non-degradative ubiquitination of TSC1 that stabilizes the TSC1–TSC2 complex to inhibit mTORC1 and T cell glycolysis [PMID:33215753], and amplifies innate immune output by K63-linked ubiquitination of ASC at K55 to assemble the NLRP3 inflammasome [PMID:34706239]. The FHA domain confers phospho-substrate selectivity, recognizing phosphorylated HPD and RPS3 to target them for degradation [PMID:31537781, PMID:38528516]. Across diverse tissues PELI1 additionally directs degradative ubiquitination of transcription factors and regulators including HNF4α, C/EBPβ, Foxp1, Mdmx, and IRF5, linking it to cardiac, hepatic, and tumor-associated phenotypes [PMID:38346961, PMID:33017390, PMID:39618410, PMID:29523541, PMID:36822176].","teleology":[{"year":2009,"claim":"Established PELI1 as a substrate-specific E3 ligase in TLR signaling by showing it K63-ubiquitinates RIP1 to drive TRIF- but not MyD88-dependent NF-κB activation, defining its pathway selectivity.","evidence":"Co-IP, in vitro ubiquitination, and knockout mice across TLR contexts","pmids":["19734906"],"confidence":"High","gaps":["Did not map the ubiquitination site on RIP1","FHA/RING domain contributions not dissected here"]},{"year":2011,"claim":"Showed PELI1 also acts as a brake on NF-κB by K48-degradative ubiquitination of c-Rel, explaining the spontaneous autoimmunity of Peli1-deficient mice and revealing dual activating/inhibitory roles.","evidence":"Knockout mice, ubiquitination assays, nuclear fractionation, T cell activation assays","pmids":["21874024"],"confidence":"High","gaps":["c-Rel ubiquitination site not mapped","Mechanism distinguishing activating vs degradative targeting unresolved"]},{"year":2013,"claim":"Extended PELI1's reach to MAPK signaling by demonstrating TRAF3 degradation enables microglial TLR responses, with genetic epistasis confirming TRAF3 as the relevant target.","evidence":"Knockout mice, EAE model, TRAF3 protein analysis, Traf3 ablation rescue","pmids":["23603814"],"confidence":"High","gaps":["Direct in vitro TRAF3 ubiquitination not shown","Ubiquitin linkage type on TRAF3 unspecified"]},{"year":2015,"claim":"Identified PELI1 as a negative regulator of type I interferon in the CNS, broadening its innate immune function to antiviral responses.","evidence":"Peli1-KO mice, intranasal VSV infection, IFN-β and viral titer assays","pmids":["26131354"],"confidence":"Medium","gaps":["Molecular target downstream of E3 activity not identified","Mechanism of IFN-I suppression unresolved"]},{"year":2017,"claim":"Defined PELI1 as a necroptosis driver by mapping kinase-dependent K63 ubiquitination of RIPK1-K115 that promotes necrosome formation, establishing a positive role in regulated necrosis.","evidence":"Site-directed mutagenesis (K115), RIPK1-RIPK3 Co-IP, kinase inhibitor experiments, KO cells/mice","pmids":["29078411"],"confidence":"High","gaps":["Relationship between c-FLIP mRNA maintenance and ligase activity unclear","How kinase activity gates ubiquitination not structurally resolved"]},{"year":2018,"claim":"Revealed PELI1 also restrains necroptosis by FHA-dependent recognition of phospho-T182 RIP3 and K48 ubiquitination at K363, showing opposing control of the RIPK1 vs RIP3 nodes.","evidence":"Reconstituted in vitro ubiquitination, T182/K363 mutants, proteasome inhibitors, FHA mapping; replicated by companion paper","pmids":["29883609","30269743"],"confidence":"High","gaps":["Determinant choosing K63-RIPK1 vs K48-RIP3 outcomes not defined","In vivo balance of the two activities not resolved"]},{"year":2018,"claim":"Showed PELI1 suppresses noncanonical NF-κB via K48 ubiquitination of NIK in B cells, linking its loss to lupus-like autoantibody production.","evidence":"Co-IP, ubiquitination assays, B cell-specific conditional KO, lupus model","pmids":["29555915"],"confidence":"High","gaps":["NIK ubiquitination site not mapped","Recruitment mechanism to NIK unresolved"]},{"year":2018,"claim":"Connected PELI1 to tumor suppression control by non-degradative ubiquitination of Mdmx that drives its cytoplasmic retention and sustains p53 activity.","evidence":"Co-IP, in vitro binding/ubiquitination, subcellular fractionation, Peli1-KO Myc tumor model","pmids":["29523541"],"confidence":"High","gaps":["Ubiquitin linkage on Mdmx not characterized","Direct effect on p53 binding partners not dissected"]},{"year":2019,"claim":"Demonstrated FHA-domain phospho-recognition as a general PELI1 substrate-selection mechanism by showing it degrades STK33-phosphorylated HPD, with TTC36 antagonizing recruitment.","evidence":"Co-IP, in vitro kinase and ubiquitination assays, Ttc36-KO tyrosinemia model","pmids":["31537781"],"confidence":"High","gaps":["HPD ubiquitination site not mapped","Generalizability of phospho-degron logic to other substrates not tested here"]},{"year":2019,"claim":"Implicated the PELI1 RING domain in ER-stress signaling through direct Hsp90 binding that enhances IRE1α phosphorylation in cardiac endothelium.","evidence":"Domain-level Co-IP, endothelial-specific KO, IRE1α phosphorylation and permeability assays in diabetic mice","pmids":["31260751"],"confidence":"Medium","gaps":["Mechanistic link from Hsp90 binding to IRE1α activation not reconstituted","Ubiquitination role, if any, undefined"]},{"year":2020,"claim":"Placed PELI1 in metabolic reprogramming by non-degradative ubiquitination of TSC1 that stabilizes TSC1-TSC2 and inhibits mTORC1, controlling T cell glycolysis and antitumor immunity.","evidence":"Ubiquitination assays, TSC1-TSC2 Co-IP, mTORC1 readouts in KO T cells, tumor models","pmids":["33215753"],"confidence":"High","gaps":["TSC1 ubiquitination site/linkage not mapped","How non-degradative chains promote dimerization unresolved"]},{"year":2020,"claim":"Linked PELI1 to neurodegeneration by degrading C/EBPβ to limit CD36 and microglial Aβ phagocytosis, identifying a transcription-factor substrate in the CNS.","evidence":"Co-IP, ubiquitination assay, Peli1-KO microglia, 5×FAD model, phagocytosis assays","pmids":["33017390"],"confidence":"High","gaps":["C/EBPβ ubiquitination site not mapped","Direct vs indirect CD36 regulation not fully separated"]},{"year":2021,"claim":"Showed PELI1 activates the NLRP3 inflammasome specifically by K63 ubiquitination of ASC-K55, promoting ASC oligomerization and IL-1β maturation.","evidence":"K55 mutagenesis, ASC-NLRP3 Co-IP, oligomerization assays, KO mice with multiple inflammasome inducers","pmids":["34706239"],"confidence":"High","gaps":["Basis for NLRP3 selectivity over other inflammasomes unresolved","Upstream signal triggering ASC ubiquitination unclear"]},{"year":2021,"claim":"Positioned PELI1 upstream of Tfh differentiation via c-Rel/ICOS/PI3K-AKT/Klf2, integrating its NF-κB control with T cell fate.","evidence":"Bone marrow chimeras, flow cytometry, PI3K-AKT assays, Klf2 reconstitution rescue, Peli1-KO mice","pmids":["33707688"],"confidence":"Medium","gaps":["No direct ubiquitination substrate in this axis identified","ICOS regulation shown as downstream of c-Rel, not direct"]},{"year":2021,"claim":"Confirmed the PELI1–NIK–noncanonical NF-κB axis in cancer, where NIK degradation lowers Bclxl and sensitizes esophageal cancer cells to radiation.","evidence":"Ubiquitination/stability assays, noncanonical NF-κB reporters, PELI1 KD/KO, in vivo irradiation model","pmids":["34738714"],"confidence":"Medium","gaps":["Single-lab confirmation of NIK axis in cancer context","NIK ubiquitination site not mapped"]},{"year":2022,"claim":"Extended PELI1 to autophagy regulation by RING-domain-dependent K63 ubiquitination of P62-K7 that blocks P62 dimerization and autophagic flux in cardiac I/R.","evidence":"Co-IP, GST-pulldown, K7 mutagenesis, LC3/P62 flux assays, KO mice with I/R model","pmids":["36179399"],"confidence":"High","gaps":["Effect on broader autophagy machinery not assessed","Tissue specificity of P62 targeting unclear"]},{"year":2023,"claim":"Identified PELI1 as a driver of macrophage M1 polarization through K63 ubiquitination and nuclear translocation of IRF5 in cardiac I/R injury.","evidence":"Ubiquitination assays, IRF5 nuclear fractionation, macrophage-specific KO, I/R model, M1/M2 flow cytometry","pmids":["36822176"],"confidence":"Medium","gaps":["IRF5 ubiquitination site not mapped","Single-lab finding"]},{"year":2023,"claim":"Revealed a PELI1-EGFR positive feedback loop where EGFR phosphorylates and activates PELI1, which K63-ubiquitinates and stabilizes EGFR to promote breast cancer metastasis.","evidence":"Co-IP, phospho-site mapping (Y154/T264), K63 linkage assays, migration/invasion and metastasis models","pmids":["36841821"],"confidence":"Medium","gaps":["EGFR ubiquitination site not mapped","Single-lab reciprocal regulation model"]},{"year":2023,"claim":"Connected cardiomyocyte PELI1 to fibrosis through NF-κB/AP-1-driven miR-494-3p in exosomes that activate fibroblasts via PTEN suppression.","evidence":"CM-conditional KO mice, miRNA array, exosome isolation, NF-κB/AP-1 reporters, PTEN/AKT assays","pmids":["36520055"],"confidence":"Medium","gaps":["No direct ubiquitination substrate in this axis","Single-lab exosomal mechanism"]},{"year":2024,"claim":"Expanded PELI1's substrate repertoire to metabolic transcription factor HNF4α (K307/K309) in heart, linking its activity to fatty acid oxidation and cardiac hypertrophy.","evidence":"Co-IP, mass spectrometry, K307/K309 mutagenesis, RNA-seq, AAV9-HNF4α rescue, TAC model","pmids":["38346961"],"confidence":"High","gaps":["Ubiquitin linkage type not specified","Single-lab cardiac context"]},{"year":2024,"claim":"Identified Foxp1 degradation as the mechanism by which PELI1 promotes IL-6-driven macrophage activation and pulmonary vascular remodeling.","evidence":"Proteomics, Co-IP, Foxp1 stability assays, myeloid Peli1/Foxp1 KO mice, hypoxia PH model","pmids":["39618410"],"confidence":"Medium","gaps":["Foxp1 ubiquitination site/linkage not mapped","Partial epistasis suggests additional substrates"]},{"year":2024,"claim":"Showed FHA-dependent K48 ubiquitination of RPS3 by PELI1 activates PI3K/Akt/GSK3β and weakens RPS3-mediated p53 protection in pancreatic cancer.","evidence":"Co-IP, GST-pulldown, ubiquitination assays, immunofluorescence, xenograft and metastasis models","pmids":["38528516"],"confidence":"Medium","gaps":["RPS3 ubiquitination site not mapped","Single-lab finding"]},{"year":2024,"claim":"Added IRAK2 as a K63-ubiquitination target whose degradation underlies PELI1's anti-inflammatory effect in airway epithelium via p38-MAPK/NF-κB suppression.","evidence":"CRISPR KO, AAV6.2 overexpression, ubiquitination assays, IRAK2 re-expression rescue, MAPK/NF-κB assays","pmids":["40986758"],"confidence":"Medium","gaps":["IRAK2 ubiquitination site not mapped","K63-degradative mechanism atypical and not reconstituted"]},{"year":2024,"claim":"Placed PELI1 upstream of TCF-1 in CD4+ T cell lineage choice through ubiquitination-mediated TCF-1 degradation.","evidence":"Co-IP, ubiquitination assays, TCF-1 rescue, T cell subset flow cytometry","pmids":["39617092"],"confidence":"Low","gaps":["TCF-1 ubiquitination site and chain type not mapped","Single-lab, mechanism not reconstituted"]},{"year":2024,"claim":"Identified INPP5J as a degradative target supporting PELI1's pro-tumorigenic role in pancreatic cancer.","evidence":"Co-IP, ubiquitination assays, gain/loss-of-function, xenograft, INPP5J rescue","pmids":["38685520"],"confidence":"Medium","gaps":["INPP5J ubiquitination site/linkage not mapped","Single-lab finding"]},{"year":2025,"claim":"Linked PELI1 to atherosclerosis through K48 degradation of YB-1 limiting NLRP3 activation, and showed METTL3/YTHDC2 m6A control of Peli1 mRNA, adding an upstream regulatory layer.","evidence":"Ubiquitination assays, YB-1 stability, m6A and YTHDC2 co-precipitation, atherosclerosis model with rescue","pmids":["40102597"],"confidence":"Medium","gaps":["YB-1 ubiquitination site not mapped","Single-lab m6A regulatory mechanism"]},{"year":2025,"claim":"Implicated PELI1 in microglial exosome release driving neurotoxic astrocyte conversion, with a feedback loop upregulating microglial Peli1.","evidence":"Microglial depletion, exosome blockade, exosome injection, Peli1 inhibition, astrocyte phenotyping","pmids":["40816423"],"confidence":"Low","gaps":["Direct biochemical mechanism by which PELI1 controls exosome release not characterized","Single-lab functional inference"]},{"year":2026,"claim":"Connected PELI1 to ferroptosis via FTH1 degradation in a P53/PELI1/FTH1 axis activated by hyperandrogenism in PCOS.","evidence":"Transcriptome sequencing, cellular ubiquitination assays, PCOS mouse model, deferoxamine rescue","pmids":["41620040"],"confidence":"Low","gaps":["FTH1 ubiquitination inferred, not fully reconstituted","Mechanistic chain from p53 to PELI1 not established"]},{"year":null,"claim":"How PELI1 selects among activating K63 versus degradative K48 chemistry on different substrates, and what governs its tissue-specific substrate repertoire, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model explaining linkage-type switching","Substrate-specificity determinants beyond FHA phospho-recognition undefined","Upstream signals dictating context-specific substrate choice unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,3,4,5,9,11,16]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,4,5,9,11,14,16,18]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3,11,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,9,22]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,9,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,6,15]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,11,15,19,25]},{"term_id":"R-HSA-162582","term_label":"Signal 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Involved in the TLR and IL-1 signaling pathways via interaction with the complex containing IRAK kinases and TRAF6 (PubMed:12496252, PubMed:17675297). Acts as a positive regulator of inflammatory response in microglia through activation of NF-kappa-B and MAP kinase (By similarity). Mediates 'Lys-63'-linked polyubiquitination of IRAK1 allowing subsequent NF-kappa-B activation (PubMed:12496252, PubMed:17675297). Conjugates 'Lys-63'-linked ubiquitin chains to the adapter protein ASC/PYCARD, which in turn is crucial for NLRP3 inflammasome activation (PubMed:34706239). Mediates 'Lys-48'-linked polyubiquitination of RIPK3 leading to its subsequent proteasome-dependent degradation; preferentially recognizes and mediates the degradation of the 'Thr-182' phosphorylated form of RIPK3 (PubMed:29883609). Negatively regulates necroptosis by reducing RIPK3 expression (PubMed:29883609). Mediates 'Lys-63'-linked ubiquitination of RIPK1 (PubMed:29883609). Following phosphorylation by ATM, catalyzes 'Lys-63'-linked ubiquitination of NBN, promoting DNA repair via homologous recombination (PubMed:30952868). Negatively regulates activation of the metabolic mTORC1 signaling pathway by mediating 'Lys-63'-linked ubiquitination of mTORC1-inhibitory protein TSC1 and thereby promoting TSC1/TSC2 complex stability (PubMed:33215753)","subcellular_location":"Chromosome","url":"https://www.uniprot.org/uniprotkb/Q96FA3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PELI1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PELI1","total_profiled":1310},"omim":[{"mim_id":"614798","title":"PELLINO E3 UBIQUITIN PROTEIN LIGASE 2; PELI2","url":"https://www.omim.org/entry/614798"},{"mim_id":"614797","title":"PELLINO E3 UBIQUITIN PROTEIN LIGASE 1; PELI1","url":"https://www.omim.org/entry/614797"},{"mim_id":"609827","title":"PELLINO E3 UBIQUITIN PROTEIN LIGASE 3; PELI3","url":"https://www.omim.org/entry/609827"},{"mim_id":"602635","title":"DEAF1 TRANSCRIPTION FACTOR; DEAF1","url":"https://www.omim.org/entry/602635"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"},{"location":"Basal body","reliability":"Supported"},{"location":"Intermediate filaments","reliability":"Additional"},{"location":"Centriolar satellite","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":215.9}],"url":"https://www.proteinatlas.org/search/PELI1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q96FA3","domains":[{"cath_id":"-","chopping":"15-120_128-260","consensus_level":"high","plddt":92.9264,"start":15,"end":260},{"cath_id":"-","chopping":"264-409","consensus_level":"high","plddt":91.2276,"start":264,"end":409}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FA3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FA3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FA3-F1-predicted_aligned_error_v6.png","plddt_mean":89.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PELI1","jax_strain_url":"https://www.jax.org/strain/search?query=PELI1"},"sequence":{"accession":"Q96FA3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96FA3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96FA3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FA3"}},"corpus_meta":[{"pmid":"19734906","id":"PMC_19734906","title":"Peli1 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Animal","url":"https://pubmed.ncbi.nlm.nih.gov/40588681","citation_count":4,"is_preprint":false},{"pmid":"33470690","id":"PMC_33470690","title":"Immune-related genes STIM1, ITPKC and PELI1 polymorphisms are associated with risk of colorectal cancer.","date":"2021","source":"European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP)","url":"https://pubmed.ncbi.nlm.nih.gov/33470690","citation_count":4,"is_preprint":false},{"pmid":"36606193","id":"PMC_36606193","title":"Bcl-6-dependent risk stratification by nuclear expression of Peli1 in diffuse large B-cell lymphoma.","date":"2022","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36606193","citation_count":3,"is_preprint":false},{"pmid":"30269743","id":"PMC_30269743","title":"Regulation of RIP3 protein stability by PELI1-mediated proteasome-dependent degradation.","date":"2018","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/30269743","citation_count":3,"is_preprint":false},{"pmid":"37657587","id":"PMC_37657587","title":"Aberrant expression of PELI1 caused by Jagged1 accelerates the malignant phenotype of pancreatic cancer.","date":"2023","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/37657587","citation_count":2,"is_preprint":false},{"pmid":"40986758","id":"PMC_40986758","title":"IRAK2 ubiquitination mediated by PELI1 regulates airway epithelial function and alleviates pediatric asthma.","date":"2026","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40986758","citation_count":1,"is_preprint":false},{"pmid":"40407238","id":"PMC_40407238","title":"PELI1 silencing delays intervertebral disc degeneration by impeding nucleus pulposus cell death.","date":"2025","source":"Connective tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/40407238","citation_count":1,"is_preprint":false},{"pmid":"40070794","id":"PMC_40070794","title":"hsa_circ_0004846 enhances the malignant phenotype of papillary thyroid carcinoma cells via the miR‑142‑3p/PELI1 axis.","date":"2025","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/40070794","citation_count":1,"is_preprint":false},{"pmid":"41143725","id":"PMC_41143725","title":"Adipose-derived MSC extracellular vesicles ameliorate sepsis by reprogramming macrophages via miR-21-5p targeting PELI1.","date":"2025","source":"Biomolecules & biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/41143725","citation_count":1,"is_preprint":false},{"pmid":"39617092","id":"PMC_39617092","title":"Knockdown of PELI1 promotes Th2 and Treg cell differentiation in juvenile idiopathic arthritis.","date":"2024","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/39617092","citation_count":0,"is_preprint":false},{"pmid":"41562077","id":"PMC_41562077","title":"PELI1 in human cancers: a pan-cancer exploration of its molecular function, clinical significance, and immunomodulatory roles.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41562077","citation_count":0,"is_preprint":false},{"pmid":"41620040","id":"PMC_41620040","title":"E3 ubiquitin ligase PELI1 promotes ferroptosis in granulosa cells in PCOS by degrading Fth1.","date":"2026","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/41620040","citation_count":0,"is_preprint":false},{"pmid":"41481033","id":"PMC_41481033","title":"miR-369-3p Regulates Microglia Polarization and Neuroinflammation in Traumatic Spinal Cord Injury by Targeting PELI1.","date":"2026","source":"Global spine journal","url":"https://pubmed.ncbi.nlm.nih.gov/41481033","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":32868,"output_tokens":7634,"usd":0.106557,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16825,"output_tokens":7765,"usd":0.139125,"stage2_stop_reason":"end_turn"},"total_usd":0.245682,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"Peli1 (E3 ubiquitin ligase) binds to and ubiquitinates RIP1, mediating K63-linked ubiquitination to promote IKK activation downstream of the TLR3/TLR4 adaptor TRIF, but is dispensable for IKK-NF-κB activation by MyD88-dependent TLRs and IL-1R.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, genetic knockout mice, cytokine induction assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding and ubiquitination assays with genetic KO validation, replicated in multiple TLR contexts\",\n      \"pmids\": [\"19734906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Peli1 mediates K48-linked ubiquitination of c-Rel (NF-κB family member), targeting it for degradation; Peli1 deficiency causes nuclear accumulation of c-Rel and hyperactivation of T cells, leading to spontaneous autoimmunity.\",\n      \"method\": \"Genetic knockout mice, ubiquitination assays, nuclear fractionation/immunoblot, T cell activation assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — K48 ubiquitination of c-Rel established with ubiquitination assays and nuclear accumulation confirmed by fractionation in KO cells, supported by in vivo autoimmunity phenotype\",\n      \"pmids\": [\"21874024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Peli1 promotes degradation of TRAF3 (a potent inhibitor of MAPK activation) in microglia via ubiquitin-mediated proteolysis, thereby enabling TLR pathway-driven chemokine and cytokine induction; ablation of TRAF3 restores microglial activation in Peli1-deficient mice.\",\n      \"method\": \"Genetic knockout mice, EAE model, TRAF3 protein level analysis, epistasis rescue experiment (Traf3 ablation in Peli1-KO)\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis rescue (Traf3-/- restores phenotype in Peli1-KO) plus protein degradation assays in primary microglia\",\n      \"pmids\": [\"23603814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PELI1 mediates K63-linked ubiquitination of RIPK1 at lysine 115 in a kinase-activity-dependent manner during necroptosis, promoting necrosome formation (RIPK1-RIPK3 interaction) and RIPK3/MLKL activation; separately, PELI1 maintains c-FLIP mRNA levels, and its deficiency sensitizes cells to apoptosis.\",\n      \"method\": \"Ubiquitination assays with site-directed mutagenesis (K115), co-immunoprecipitation of RIPK1-RIPK3, RIPK1 kinase inhibitor experiments, knockout cell lines and mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-specific mutagenesis (K115), kinase-dependent ubiquitination, and necrosome assembly assays with multiple orthogonal methods\",\n      \"pmids\": [\"29078411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PELI1 selectively targets kinase-active RIP3 (phosphorylated on T182) for K48-linked polyubiquitylation at K363 via interaction with the PELI1 FHA domain, leading to proteasome-dependent RIP3 degradation and prevention of necroptosis triggered by RIP3 hyperactivation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, site-directed mutagenesis (T182, K363), proteasome inhibitor experiments, patient TEN keratinocyte samples\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro ubiquitination with phospho-mimetic and K363 mutants, FHA domain interaction mapped, replicated by companion paper (PMID:30269743)\",\n      \"pmids\": [\"29883609\", \"30269743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Peli1 functions as an E3 ligase for NF-κB-inducing kinase (NIK), mediating K48-linked ubiquitination and proteasomal degradation of NIK, thereby suppressing noncanonical NF-κB signaling in B cells and restraining autoantibody production in lupus-like disease.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, B cell-specific conditional knockout mice, lupus disease model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct ubiquitination of NIK shown with K48 linkage, genetic rescue in B cell-specific KO with noncanonical NF-κB readouts\",\n      \"pmids\": [\"29555915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Peli1 binds Mdmx in vitro and in vivo and promotes non-degradative ubiquitination of Mdmx, causing its cytoplasmic localization; Peli1 loss or knockdown induces nuclear localization of Mdmx and suppresses p53 activity, and Peli1-null mice show accelerated Myc-induced tumorigenesis associated with reduced p53 function.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, ubiquitination assay, subcellular fractionation, Peli1-knockout mice with Myc-driven tumor model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct in vitro binding and ubiquitination plus subcellular fractionation with functional p53 readout in KO mice, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"29523541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Peli1 FHA domain binds to phosphorylated HPD (T382 phosphorylated by STK33) and mediates polyubiquitylation and degradation of HPD; TTC36 competes with STK33 to reduce HPD phosphorylation and thus prevents Peli1 recruitment and HPD degradation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, ubiquitination assay, Ttc36 knockout mice with tyrosinemia phenotype\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — FHA domain-phospho interaction mapped, in vitro ubiquitination confirmed, in vivo genetic model with metabolic phenotype\",\n      \"pmids\": [\"31537781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Peli1 Ring domain directly binds Hsp90, and this interaction enhances IRE1α phosphorylation in cardiac microvascular endothelial cells, promoting ER stress and microvascular injury; Peli1 deficiency in endothelial cells alleviates diabetes-induced cardiac microvascular permeability.\",\n      \"method\": \"Co-immunoprecipitation (Ring domain-Hsp90), endothelial cell-specific Peli1 knockout, IRE1α phosphorylation assays, permeability assays in diabetic mouse model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — domain-level Co-IP and functional KO, but mechanistic link between Hsp90 binding and IRE1α activation not fully reconstituted\",\n      \"pmids\": [\"31260751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Peli1 mediates non-degradative ubiquitination of TSC1, promoting TSC1-TSC2 dimerization and TSC2 stabilization, thereby inhibiting mTORC1 activity; Peli1 ablation in T cells markedly increases glycolysis via mTORC1 activation and enhances antitumor immunity.\",\n      \"method\": \"Ubiquitination assays, Co-immunoprecipitation of TSC1-TSC2, mTORC1 activity assays, Peli1-knockout T cells, tumor models\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ubiquitination of TSC1 mapped, TSC1-TSC2 dimerization confirmed by Co-IP, mTORC1 functional readout in KO T cells with multiple orthogonal methods\",\n      \"pmids\": [\"33215753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Peli1 directly ubiquitinates C/EBPβ (a transcription factor for scavenger receptor CD36), promoting its degradation; Peli1 loss increases C/EBPβ protein levels and CD36 expression, enhancing microglial Aβ phagocytosis and reducing Aβ deposition in 5×FAD mice.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Peli1-knockout microglia, 5×FAD mouse model, phagocytosis assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct E3-substrate ubiquitination shown, C/EBPβ-CD36 axis confirmed, in vivo Aβ deposition phenotype in KO model\",\n      \"pmids\": [\"33017390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Peli1 conjugates K63-linked ubiquitin chains onto lysine 55 of ASC (inflammasome adaptor), facilitating ASC/NLRP3 interaction and ASC oligomerization, thereby promoting NLRP3 inflammasome activation and IL-1β maturation; this is specific to NLRP3 (not Aim2, NLRP1, or NLRC4 inflammasomes).\",\n      \"method\": \"Ubiquitination assays with site-directed mutagenesis (K55 of ASC), co-immunoprecipitation (ASC-NLRP3), ASC oligomerization assays, Peli1-knockout mice with peritonitis/LPS shock models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — K55 site-specific ubiquitination with mutagenesis, ASC-NLRP3 interaction and oligomerization measured, in vivo KO with multiple inflammasome inducers tested\",\n      \"pmids\": [\"34706239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Peli1 deficiency promotes c-Rel-mediated inducible T-cell costimulator (ICOS) expression; increased ICOS activates PI3K-AKT signaling, suppressing Klf2 expression to promote T follicular helper (Tfh) cell differentiation; reconstitution of Klf2 abolishes the Tfh differentiation difference between WT and Peli1-KO cells.\",\n      \"method\": \"Bone marrow chimeric experiments, flow cytometry, PI3K-AKT signaling assays, Klf2 reconstitution rescue experiments, Peli1-KO mice\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis rescue (Klf2 reconstitution) established pathway position; ICOS upregulation mechanistically linked to c-Rel, but direct ubiquitination of ICOS not shown\",\n      \"pmids\": [\"33707688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PELI1 mediates K48-linked polyubiquitination and proteasomal degradation of NF-κB-inducing kinase (NIK), thereby inhibiting noncanonical NF-κB pathway activation and reducing Bclxl expression, which sensitizes esophageal squamous cancer cells to ionizing radiation-induced apoptosis.\",\n      \"method\": \"Ubiquitination assays, NIK protein stability assays, noncanonical NF-κB reporter assays, PELI1 KD/KO in cancer cells, in vivo tumor irradiation model\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — K48 ubiquitination of NIK shown, pathway consequence (Bclxl/apoptosis) measured, single lab with multiple methods\",\n      \"pmids\": [\"34738714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Peli1 (via its Ring domain) directly interacts with P62/sequestosome-1 and promotes K63-linked ubiquitination of P62 at K7, inhibiting P62 dimerization and autophagic degradation, thereby impairing autophagy flux during myocardial ischemia/reperfusion injury.\",\n      \"method\": \"Co-immunoprecipitation, GST-pulldown, in vitro ubiquitination with site mutagenesis (K7), LC3/P62 flux assays, Peli1-KO mice with I/R model\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — GST-pulldown plus Co-IP map domain interaction, K7 mutagenesis establishes site, autophagy flux assay with KO in vivo\",\n      \"pmids\": [\"36179399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Peli1 promotes K63-linked ubiquitination and nuclear translocation of IRF5 in macrophages, driving M1 polarization; Peli1 deficiency in macrophages reduces IRF5 nuclear translocation, suppresses M1 polarization, and alleviates myocardial ischemia/reperfusion injury.\",\n      \"method\": \"Ubiquitination assays, nuclear fractionation for IRF5, macrophage-specific Peli1 conditional knockout, I/R mouse model, flow cytometry for M1/M2 markers\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — K63 ubiquitination of IRF5 and nuclear translocation shown, in vivo macrophage-specific KO with disease model, single lab\",\n      \"pmids\": [\"36822176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Peli1 binds HNF4α via its RING-like domain and promotes HNF4α ubiquitination at residues K307 and K309, leading to HNF4α degradation, reduced fatty acid oxidation gene expression, and exacerbated cardiac hypertrophy; HNF4α inhibition abolishes the cardioprotective effect of Peli1 knockout.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay with K307/K309 mutagenesis, RNA-seq, FAO stress assay, rAAV9-HNF4α delivery, Peli1 KO mice with TAC model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mass spectrometry identified ubiquitination sites confirmed by mutagenesis, domain interaction mapped by Co-IP, in vivo rescue with AAV-HNF4α\",\n      \"pmids\": [\"38346961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Peli1 facilitates ubiquitination and proteasomal degradation of Foxp1 in macrophages, relieving Foxp1-mediated transcriptional inhibition of IL-6, thus promoting macrophage activation and IL-6-driven pulmonary vascular remodeling; myeloid Foxp1 deficiency partially eliminates the protective effect of myeloid Peli1 deficiency in pulmonary hypertension.\",\n      \"method\": \"Proteomic analysis, co-immunoprecipitation, Foxp1 stability assays, myeloid-specific Peli1-KO and Foxp1-KO mice, hypoxia-induced PH model, IL-6 transcription assays\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (Foxp1 KO partially reverses Peli1 KO protection), ubiquitination/degradation of Foxp1 shown, single lab\",\n      \"pmids\": [\"39618410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PELI1 interacts with Ribosomal Protein S3 (RPS3) through its FHA domain and promotes K48-linked polyubiquitination and degradation of RPS3, which activates the PI3K/Akt/GSK3β signaling pathway and reduces RPS3-mediated protection of p53 from MDM2-dependent degradation, thereby promoting pancreatic cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, GST-pulldown, ubiquitination assays, immunofluorescence co-localization, in vivo xenograft and liver metastasis models\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — FHA domain-RPS3 interaction mapped by GST-pulldown and Co-IP, K48 ubiquitination demonstrated, downstream signaling pathway confirmed, single lab\",\n      \"pmids\": [\"38528516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PELI1 mediates K63-linked ubiquitination and degradation of IRAK2 in airway epithelial cells; IRAK2 overexpression reverses the anti-inflammatory effect of PELI1 overexpression by activating p38-MAPK/NF-κB signaling.\",\n      \"method\": \"CRISPR/Cas9 KO, AAV6.2 overexpression in vivo, ubiquitination assays, epistasis rescue (IRAK2 re-expression), MAPK/NF-κB signaling assays\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — K63 ubiquitination of IRAK2 shown, genetic rescue confirms pathway epistasis, single lab\",\n      \"pmids\": [\"40986758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Peli1 promotes miR-494-3p expression via NF-κB/AP-1 transcriptional activation in cardiomyocytes under mechanical stretch; cardiomyocyte-derived exosomes enriched with miR-494-3p activate cardiac fibroblasts by targeting PTEN, amplifying AKT, SMAD2/3, and ERK phosphorylation, thereby contributing to cardiac fibrosis.\",\n      \"method\": \"CM-conditional Peli1 knockout mice, miRNA microarray, exosome isolation, NF-κB/AP-1 reporter assays, PTEN/AKT pathway assays in cardiac fibroblasts\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Peli1 conditional KO with exosome fractionation and miRNA array, NF-κB/AP-1 link to miR-494-3p shown, single lab\",\n      \"pmids\": [\"36520055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PELI1 mediates K48-linked ubiquitination and degradation of YB-1 in macrophages, preventing NLRP3 inflammasome activation; YTHDC2-recognized m6A modification of Peli1 mRNA (mediated by METTL3) promotes Peli1 mRNA degradation, reducing Peli1 protein levels during atherosclerosis.\",\n      \"method\": \"Ubiquitination assays, YB-1 stability assays, m6A methylation assay, YTHDC2 co-precipitation, in vivo atherosclerosis model with rescue experiments\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ubiquitination of YB-1 and m6A regulation of Peli1 mRNA both demonstrated, single lab, rescue experiments included\",\n      \"pmids\": [\"40102597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PELI1 interacts with EGFR; EGFR activation phosphorylates PELI1 at Tyr154 and Thr264, activating its E3 ubiquitin ligase activity; reciprocally, PELI1 promotes K63-linked polyubiquitination of EGFR to enhance EGFR stability, creating a positive feedback loop that promotes breast cancer metastasis.\",\n      \"method\": \"Co-immunoprecipitation, phospho-site mapping, ubiquitination assays, K63-linkage specific assays, breast cancer cell migration/invasion assays, in vivo metastasis model\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal regulation (EGFR phosphorylates PELI1; PELI1 ubiquitinates EGFR) shown by Co-IP and ubiquitination assays, single lab\",\n      \"pmids\": [\"36841821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PELI1 interacts with INPP5J via Co-immunoprecipitation and promotes ubiquitination and proteasomal degradation of INPP5J in pancreatic cancer cells; INPP5J overexpression reverses the pro-tumorigenic effects of PELI1 overexpression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, gain/loss-of-function experiments, xenograft model, epistasis rescue with INPP5J overexpression\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and ubiquitination shown, epistasis confirmed by rescue, single lab\",\n      \"pmids\": [\"38685520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Peli1 is identified as a key regulator of microglial exosome release; Peli1 inhibition reduces microglial activation and the generation of proinflammatory exosomes that drive neurotoxic astrocyte conversion; a feedback loop was identified where neurotoxic astrocytes upregulate Peli1 expression in microglia.\",\n      \"method\": \"PLX3397 microglial depletion, GW4869 exosome secretion blockade, purified exosome injection in vivo, Peli1 inhibition in microglia, astrocyte phenotype assays\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — exosome functional data is strong but direct mechanism by which Peli1 controls exosome release is not biochemically characterized; single lab\",\n      \"pmids\": [\"40816423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Peli1 negatively regulates type I interferon (IFN-β) induction in microglia in response to TLR ligands and vesicular stomatitis virus; Peli1-deficient mice show heightened CNS IFN-I responses and reduced brain viral titers after intranasal VSV infection.\",\n      \"method\": \"Peli1 genetic knockout mice, intranasal VSV infection, IFN-β measurement in microglia in vitro and CNS in vivo, viral titer assay\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic KO with defined IFN-I readout in primary microglia and in vivo, but molecular mechanism not resolved beyond E3 ligase activity, single lab\",\n      \"pmids\": [\"26131354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PELI1 promotes ubiquitination and degradation of FTH1 (ferritin heavy chain) in ovarian granulosa cells, contributing to ferroptosis; the P53/PELI1/FTH1 pathway is activated by hyperandrogenism in PCOS, and iron death inhibitor deferoxamine alleviates follicular development disorders.\",\n      \"method\": \"Transcriptome sequencing, cellular ubiquitination assays, PCOS mouse model, iron death inhibitor rescue experiments\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ubiquitination of FTH1 inferred from transcriptomic and cellular data, mechanistic chain not fully reconstituted, single lab\",\n      \"pmids\": [\"41620040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PELI1 interacts with TCF-1 and promotes its ubiquitination and degradation; inhibition of TCF-1 reduces the effects of PELI1 knockdown on CD4+ T cell differentiation toward Th2 and Treg cells, placing PELI1 upstream of TCF-1 in T cell lineage decisions.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, TCF-1 rescue experiments, flow cytometry for T cell subsets\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination of TCF-1 shown with rescue, but ubiquitination site and chain type not mapped, single lab\",\n      \"pmids\": [\"39617092\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PELI1 is a RING-like domain E3 ubiquitin ligase that uses its FHA domain to recognize phosphorylated substrates and its RING domain to catalyze substrate ubiquitination with multiple linkage types and functional outcomes: it mediates K63-linked ubiquitination of RIP1 (promoting TRIF-dependent NF-κB activation), K63-linked ubiquitination of RIPK1-K115 (promoting necrosome formation and necroptosis), K48-linked ubiquitination of kinase-active RIP3-K363 (targeting it for proteasomal degradation), K48-linked ubiquitination of c-Rel (limiting T cell activation), K48-linked ubiquitination of NIK (suppressing noncanonical NF-κB), K48-linked ubiquitination of TRAF3 (enabling MAPK activation in microglia), non-degradative ubiquitination of TSC1 (inhibiting mTORC1 and T cell glycolysis), K63-linked ubiquitination of ASC-K55 (promoting NLRP3 inflammasome assembly), K63-linked ubiquitination of IRF5 (driving macrophage M1 polarization), and K48-linked ubiquitination of substrates including C/EBPβ, HNF4α, Mdmx, HPD, Foxp1, P62, YB-1, IRAK2, RPS3, INPP5J, and FTH1, collectively placing PELI1 as a pleiotropic ubiquitin ligase at the intersection of TLR/innate immunity, NF-κB signaling, cell death regulation, metabolic reprogramming, and tissue homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PELI1 is a RING-like domain E3 ubiquitin ligase that operates at the intersection of TLR/innate immunity, NF-\\u03baB signaling, cell death, and metabolic control, using its FHA domain to read phosphorylated substrates and its RING domain to catalyze ubiquitin transfer with linkage-specific outcomes [#0, #4]. In TLR signaling it conjugates K63-linked chains onto RIP1 to drive TRIF-dependent IKK\\u2013NF-\\u03baB activation [#0], while shaping inflammation through degradative ubiquitination of inhibitory factors\\u2014K48-linked degradation of c-Rel to restrain T cell activation and prevent autoimmunity [#1], TRAF3 degradation to license MAPK-driven microglial activation [#2], and K48-linked degradation of NIK to suppress noncanonical NF-\\u03baB in B cells [#5]. PELI1 is a bidirectional rheostat of programmed cell death: it promotes necroptosis by K63-linked ubiquitination of RIPK1 at K115 to nucleate the RIPK1\\u2013RIPK3 necrosome [#3], yet limits it by selectively K48-ubiquitinating kinase-active RIP3 at K363 for proteasomal degradation [#4]. Beyond cell death, it controls metabolism and growth signaling through non-degradative ubiquitination of TSC1 that stabilizes the TSC1\\u2013TSC2 complex to inhibit mTORC1 and T cell glycolysis [#9], and amplifies innate immune output by K63-linked ubiquitination of ASC at K55 to assemble the NLRP3 inflammasome [#11]. The FHA domain confers phospho-substrate selectivity, recognizing phosphorylated HPD and RPS3 to target them for degradation [#7, #18]. Across diverse tissues PELI1 additionally directs degradative ubiquitination of transcription factors and regulators including HNF4\\u03b1, C/EBP\\u03b2, Foxp1, Mdmx, and IRF5, linking it to cardiac, hepatic, and tumor-associated phenotypes [#16, #10, #17, #6, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established PELI1 as a substrate-specific E3 ligase in TLR signaling by showing it K63-ubiquitinates RIP1 to drive TRIF- but not MyD88-dependent NF-\\u03baB activation, defining its pathway selectivity.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination, and knockout mice across TLR contexts\",\n      \"pmids\": [\"19734906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the ubiquitination site on RIP1\", \"FHA/RING domain contributions not dissected here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed PELI1 also acts as a brake on NF-\\u03baB by K48-degradative ubiquitination of c-Rel, explaining the spontaneous autoimmunity of Peli1-deficient mice and revealing dual activating/inhibitory roles.\",\n      \"evidence\": \"Knockout mice, ubiquitination assays, nuclear fractionation, T cell activation assays\",\n      \"pmids\": [\"21874024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"c-Rel ubiquitination site not mapped\", \"Mechanism distinguishing activating vs degradative targeting unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended PELI1's reach to MAPK signaling by demonstrating TRAF3 degradation enables microglial TLR responses, with genetic epistasis confirming TRAF3 as the relevant target.\",\n      \"evidence\": \"Knockout mice, EAE model, TRAF3 protein analysis, Traf3 ablation rescue\",\n      \"pmids\": [\"23603814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct in vitro TRAF3 ubiquitination not shown\", \"Ubiquitin linkage type on TRAF3 unspecified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified PELI1 as a negative regulator of type I interferon in the CNS, broadening its innate immune function to antiviral responses.\",\n      \"evidence\": \"Peli1-KO mice, intranasal VSV infection, IFN-\\u03b2 and viral titer assays\",\n      \"pmids\": [\"26131354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target downstream of E3 activity not identified\", \"Mechanism of IFN-I suppression unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined PELI1 as a necroptosis driver by mapping kinase-dependent K63 ubiquitination of RIPK1-K115 that promotes necrosome formation, establishing a positive role in regulated necrosis.\",\n      \"evidence\": \"Site-directed mutagenesis (K115), RIPK1-RIPK3 Co-IP, kinase inhibitor experiments, KO cells/mice\",\n      \"pmids\": [\"29078411\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between c-FLIP mRNA maintenance and ligase activity unclear\", \"How kinase activity gates ubiquitination not structurally resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed PELI1 also restrains necroptosis by FHA-dependent recognition of phospho-T182 RIP3 and K48 ubiquitination at K363, showing opposing control of the RIPK1 vs RIP3 nodes.\",\n      \"evidence\": \"Reconstituted in vitro ubiquitination, T182/K363 mutants, proteasome inhibitors, FHA mapping; replicated by companion paper\",\n      \"pmids\": [\"29883609\", \"30269743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinant choosing K63-RIPK1 vs K48-RIP3 outcomes not defined\", \"In vivo balance of the two activities not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed PELI1 suppresses noncanonical NF-\\u03baB via K48 ubiquitination of NIK in B cells, linking its loss to lupus-like autoantibody production.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, B cell-specific conditional KO, lupus model\",\n      \"pmids\": [\"29555915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NIK ubiquitination site not mapped\", \"Recruitment mechanism to NIK unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected PELI1 to tumor suppression control by non-degradative ubiquitination of Mdmx that drives its cytoplasmic retention and sustains p53 activity.\",\n      \"evidence\": \"Co-IP, in vitro binding/ubiquitination, subcellular fractionation, Peli1-KO Myc tumor model\",\n      \"pmids\": [\"29523541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin linkage on Mdmx not characterized\", \"Direct effect on p53 binding partners not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated FHA-domain phospho-recognition as a general PELI1 substrate-selection mechanism by showing it degrades STK33-phosphorylated HPD, with TTC36 antagonizing recruitment.\",\n      \"evidence\": \"Co-IP, in vitro kinase and ubiquitination assays, Ttc36-KO tyrosinemia model\",\n      \"pmids\": [\"31537781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HPD ubiquitination site not mapped\", \"Generalizability of phospho-degron logic to other substrates not tested here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Implicated the PELI1 RING domain in ER-stress signaling through direct Hsp90 binding that enhances IRE1\\u03b1 phosphorylation in cardiac endothelium.\",\n      \"evidence\": \"Domain-level Co-IP, endothelial-specific KO, IRE1\\u03b1 phosphorylation and permeability assays in diabetic mice\",\n      \"pmids\": [\"31260751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from Hsp90 binding to IRE1\\u03b1 activation not reconstituted\", \"Ubiquitination role, if any, undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed PELI1 in metabolic reprogramming by non-degradative ubiquitination of TSC1 that stabilizes TSC1-TSC2 and inhibits mTORC1, controlling T cell glycolysis and antitumor immunity.\",\n      \"evidence\": \"Ubiquitination assays, TSC1-TSC2 Co-IP, mTORC1 readouts in KO T cells, tumor models\",\n      \"pmids\": [\"33215753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TSC1 ubiquitination site/linkage not mapped\", \"How non-degradative chains promote dimerization unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked PELI1 to neurodegeneration by degrading C/EBP\\u03b2 to limit CD36 and microglial A\\u03b2 phagocytosis, identifying a transcription-factor substrate in the CNS.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, Peli1-KO microglia, 5\\u00d7FAD model, phagocytosis assays\",\n      \"pmids\": [\"33017390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"C/EBP\\u03b2 ubiquitination site not mapped\", \"Direct vs indirect CD36 regulation not fully separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed PELI1 activates the NLRP3 inflammasome specifically by K63 ubiquitination of ASC-K55, promoting ASC oligomerization and IL-1\\u03b2 maturation.\",\n      \"evidence\": \"K55 mutagenesis, ASC-NLRP3 Co-IP, oligomerization assays, KO mice with multiple inflammasome inducers\",\n      \"pmids\": [\"34706239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis for NLRP3 selectivity over other inflammasomes unresolved\", \"Upstream signal triggering ASC ubiquitination unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Positioned PELI1 upstream of Tfh differentiation via c-Rel/ICOS/PI3K-AKT/Klf2, integrating its NF-\\u03baB control with T cell fate.\",\n      \"evidence\": \"Bone marrow chimeras, flow cytometry, PI3K-AKT assays, Klf2 reconstitution rescue, Peli1-KO mice\",\n      \"pmids\": [\"33707688\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct ubiquitination substrate in this axis identified\", \"ICOS regulation shown as downstream of c-Rel, not direct\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed the PELI1\\u2013NIK\\u2013noncanonical NF-\\u03baB axis in cancer, where NIK degradation lowers Bclxl and sensitizes esophageal cancer cells to radiation.\",\n      \"evidence\": \"Ubiquitination/stability assays, noncanonical NF-\\u03baB reporters, PELI1 KD/KO, in vivo irradiation model\",\n      \"pmids\": [\"34738714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab confirmation of NIK axis in cancer context\", \"NIK ubiquitination site not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended PELI1 to autophagy regulation by RING-domain-dependent K63 ubiquitination of P62-K7 that blocks P62 dimerization and autophagic flux in cardiac I/R.\",\n      \"evidence\": \"Co-IP, GST-pulldown, K7 mutagenesis, LC3/P62 flux assays, KO mice with I/R model\",\n      \"pmids\": [\"36179399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effect on broader autophagy machinery not assessed\", \"Tissue specificity of P62 targeting unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified PELI1 as a driver of macrophage M1 polarization through K63 ubiquitination and nuclear translocation of IRF5 in cardiac I/R injury.\",\n      \"evidence\": \"Ubiquitination assays, IRF5 nuclear fractionation, macrophage-specific KO, I/R model, M1/M2 flow cytometry\",\n      \"pmids\": [\"36822176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IRF5 ubiquitination site not mapped\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a PELI1-EGFR positive feedback loop where EGFR phosphorylates and activates PELI1, which K63-ubiquitinates and stabilizes EGFR to promote breast cancer metastasis.\",\n      \"evidence\": \"Co-IP, phospho-site mapping (Y154/T264), K63 linkage assays, migration/invasion and metastasis models\",\n      \"pmids\": [\"36841821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EGFR ubiquitination site not mapped\", \"Single-lab reciprocal regulation model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected cardiomyocyte PELI1 to fibrosis through NF-\\u03baB/AP-1-driven miR-494-3p in exosomes that activate fibroblasts via PTEN suppression.\",\n      \"evidence\": \"CM-conditional KO mice, miRNA array, exosome isolation, NF-\\u03baB/AP-1 reporters, PTEN/AKT assays\",\n      \"pmids\": [\"36520055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct ubiquitination substrate in this axis\", \"Single-lab exosomal mechanism\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded PELI1's substrate repertoire to metabolic transcription factor HNF4\\u03b1 (K307/K309) in heart, linking its activity to fatty acid oxidation and cardiac hypertrophy.\",\n      \"evidence\": \"Co-IP, mass spectrometry, K307/K309 mutagenesis, RNA-seq, AAV9-HNF4\\u03b1 rescue, TAC model\",\n      \"pmids\": [\"38346961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin linkage type not specified\", \"Single-lab cardiac context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified Foxp1 degradation as the mechanism by which PELI1 promotes IL-6-driven macrophage activation and pulmonary vascular remodeling.\",\n      \"evidence\": \"Proteomics, Co-IP, Foxp1 stability assays, myeloid Peli1/Foxp1 KO mice, hypoxia PH model\",\n      \"pmids\": [\"39618410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Foxp1 ubiquitination site/linkage not mapped\", \"Partial epistasis suggests additional substrates\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed FHA-dependent K48 ubiquitination of RPS3 by PELI1 activates PI3K/Akt/GSK3\\u03b2 and weakens RPS3-mediated p53 protection in pancreatic cancer.\",\n      \"evidence\": \"Co-IP, GST-pulldown, ubiquitination assays, immunofluorescence, xenograft and metastasis models\",\n      \"pmids\": [\"38528516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RPS3 ubiquitination site not mapped\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added IRAK2 as a K63-ubiquitination target whose degradation underlies PELI1's anti-inflammatory effect in airway epithelium via p38-MAPK/NF-\\u03baB suppression.\",\n      \"evidence\": \"CRISPR KO, AAV6.2 overexpression, ubiquitination assays, IRAK2 re-expression rescue, MAPK/NF-\\u03baB assays\",\n      \"pmids\": [\"40986758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IRAK2 ubiquitination site not mapped\", \"K63-degradative mechanism atypical and not reconstituted\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed PELI1 upstream of TCF-1 in CD4+ T cell lineage choice through ubiquitination-mediated TCF-1 degradation.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, TCF-1 rescue, T cell subset flow cytometry\",\n      \"pmids\": [\"39617092\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"TCF-1 ubiquitination site and chain type not mapped\", \"Single-lab, mechanism not reconstituted\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified INPP5J as a degradative target supporting PELI1's pro-tumorigenic role in pancreatic cancer.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, gain/loss-of-function, xenograft, INPP5J rescue\",\n      \"pmids\": [\"38685520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"INPP5J ubiquitination site/linkage not mapped\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked PELI1 to atherosclerosis through K48 degradation of YB-1 limiting NLRP3 activation, and showed METTL3/YTHDC2 m6A control of Peli1 mRNA, adding an upstream regulatory layer.\",\n      \"evidence\": \"Ubiquitination assays, YB-1 stability, m6A and YTHDC2 co-precipitation, atherosclerosis model with rescue\",\n      \"pmids\": [\"40102597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"YB-1 ubiquitination site not mapped\", \"Single-lab m6A regulatory mechanism\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated PELI1 in microglial exosome release driving neurotoxic astrocyte conversion, with a feedback loop upregulating microglial Peli1.\",\n      \"evidence\": \"Microglial depletion, exosome blockade, exosome injection, Peli1 inhibition, astrocyte phenotyping\",\n      \"pmids\": [\"40816423\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct biochemical mechanism by which PELI1 controls exosome release not characterized\", \"Single-lab functional inference\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected PELI1 to ferroptosis via FTH1 degradation in a P53/PELI1/FTH1 axis activated by hyperandrogenism in PCOS.\",\n      \"evidence\": \"Transcriptome sequencing, cellular ubiquitination assays, PCOS mouse model, deferoxamine rescue\",\n      \"pmids\": [\"41620040\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"FTH1 ubiquitination inferred, not fully reconstituted\", \"Mechanistic chain from p53 to PELI1 not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PELI1 selects among activating K63 versus degradative K48 chemistry on different substrates, and what governs its tissue-specific substrate repertoire, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model explaining linkage-type switching\", \"Substrate-specificity determinants beyond FHA phospho-recognition undefined\", \"Upstream signals dictating context-specific substrate choice unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 3, 4, 5, 9, 11, 16]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 4, 5, 9, 11, 14, 16, 18]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3, 11, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 9, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 9, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 6, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 11, 15, 19, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 9, 22]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 4, 26]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 4, 5, 16, 18]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 9, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RIPK1\", \"RIPK3\", \"TRAF3\", \"NIK\", \"TSC1\", \"ASC\", \"Mdmx\", \"EGFR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}