{"gene":"CD274","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1999,"finding":"B7-H1 (CD274/PD-L1) was identified as a third B7 family member that does not bind CD28, CTLA-4, or ICOS, but co-stimulates T-cell proliferation and preferentially induces IL-10 secretion; IL-2 was required for this co-stimulatory effect.","method":"Receptor binding assays (negative for CD28/CTLA-4/ICOS), T-cell co-stimulation assays with polyclonal and allogeneic stimuli, cytokine measurement","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — original identification paper with multiple functional assays; foundational study replicated by numerous subsequent labs","pmids":["10581077"],"is_preprint":false},{"year":2002,"finding":"Tumor-associated B7-H1 (PD-L1) promotes apoptosis of antigen-specific T cells in vitro and in vivo, increasing growth of immunogenic tumors; IFN-γ upregulates B7-H1 on tumor cell surfaces; the apoptotic effect is mediated largely by receptor(s) other than PD-1.","method":"In vitro T-cell apoptosis assays with human T-cell clones, mouse P815 tumor model in vivo, immunohistochemistry on human tumor tissues, flow cytometry","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vitro and in vivo), widely replicated; seminal functional study","pmids":["12091876"],"is_preprint":false},{"year":2003,"finding":"B7-H1 binds PD-1 on activated T and B cells, inhibiting T-cell responses by inducing apoptosis and arresting cell-cycle progression; it also has a costimulatory receptor distinct from PD-1 that drives IL-10 and IFN-γ production.","method":"Receptor binding studies, T-cell functional assays, apoptosis assays","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — review synthesizing prior experimental data; findings supported by multiple earlier studies but this paper itself is a review","pmids":["12721664"],"is_preprint":false},{"year":2014,"finding":"PTEN loss increases PD-L1 cell-surface expression and mRNA levels in breast cancer cells via PI3K/AKT signaling; AKT inhibitor MK-2206 or rapamycin reduces PD-L1 expression; increased PD-L1 from PTEN loss leads to decreased T-cell proliferation and increased T-cell apoptosis in co-culture.","method":"PTEN shRNA knockdown in stable cell lines, flow cytometry, Western blot, PI3K pathway inhibitor treatment (MK-2206, rapamycin), T-cell co-culture assays","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KD, pharmacological inhibition, functional co-culture) in single lab","pmids":["24764583"],"is_preprint":false},{"year":2016,"finding":"MYC oncogene directly binds the promoter of the Pd-l1 (Cd274) gene to transcriptionally activate PD-L1 expression; MYC inactivation in mouse tumors downregulates PD-L1 and enhances antitumor immune response; forced PD-L1 expression during MYC inactivation suppresses immune response and tumor regression.","method":"ChIP (MYC binding to Cd274 promoter), genetic MYC inactivation in mouse tumor models, enforced PD-L1 expression rescue experiments, mRNA/protein measurements","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP demonstrating direct promoter binding plus genetic epistasis in vivo; multiple orthogonal methods","pmids":["26966191"],"is_preprint":false},{"year":2016,"finding":"CSN5 (COP9 signalosome 5), induced by NF-κB p65 downstream of TNF-α signaling, deubiquitinates and stabilizes PD-L1, preventing its proteasomal degradation; curcumin inhibits CSN5 and reduces PD-L1 expression.","method":"Co-immunoprecipitation, ubiquitination assays, NF-κB inhibition, CSN5 knockdown/overexpression, Western blot, pharmacological inhibition with curcumin","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assays, and pharmacological rescue in single lab with multiple orthogonal methods","pmids":["27866850"],"is_preprint":false},{"year":2017,"finding":"CMTM6 (and its closest family member CMTM4, but not other CMTM members) associates with PD-L1 protein at the cell surface, reduces PD-L1 ubiquitination, and increases PD-L1 protein half-life without affecting CD274 transcription, thereby enhancing PD-L1-mediated T-cell inhibition.","method":"Haploid genetic screen, haploid genetic modifier screen, genetic complementation, Co-immunoprecipitation, ubiquitination assays, protein half-life measurements, T-cell inhibition assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — unbiased genetic screen + reciprocal Co-IP + functional validation; multiple orthogonal methods in single rigorous study","pmids":["28813410"],"is_preprint":false},{"year":2005,"finding":"PD-L1 (CD274) expression in trophoblast cells is regulated by oxygen concentration: low oxygen rapidly downregulates CD274 mRNA (within 4-12 h), and protein levels increase with rising oxygen concentrations, paralleling in vivo expression patterns during placental development.","method":"Immunoblot of first- and second-trimester placental lysates, trophoblast cell culture under varying oxygen concentrations, mRNA quantification","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct experimental manipulation of oxygen with mRNA and protein measurements; single lab, two methods","pmids":["16251499"],"is_preprint":false},{"year":2014,"finding":"Intestinal epithelium-expressed B7-H1 (PD-L1) controls intestinal inflammation independently of adaptive immunity; using bone marrow chimeric and knockout mice, parenchymal (non-hematopoietic) B7-H1 dampens inflammation by inhibiting TNF-α production and stimulating IL-22 secretion from CD11c+CD11b+ lamina propria cells.","method":"DSS/TNBS-induced colitis models, B7-H1 knockout mice, bone marrow chimera experiments, cytokine measurement","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular and cytokine phenotype, epistasis via bone marrow chimeras; multiple orthogonal methods","pmids":["24529703"],"is_preprint":false},{"year":2011,"finding":"B7-H1 (PD-L1) overexpression in keratinocytes accelerates chemically induced squamous cell carcinoma by promoting epithelial-mesenchymal transition (EMT), as evidenced by reduced E-cadherin and elevated Slug/Twist transcription factors in B7-H1 transgenic mouse-derived keratinocytes and SCCs.","method":"B7-H1 transgenic mouse model, chemical carcinogenesis model, immunostaining for E-cadherin, Slug, and Twist","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse model with defined molecular markers of EMT; single lab","pmids":["21730022"],"is_preprint":false},{"year":2019,"finding":"Autophagy inhibition increases PD-L1 expression in gastric cancer cells through accumulation of p62/SQSTM1 and consequent NF-κB activation; NF-κB inhibition or p62/SQSTM1 knockdown attenuates PD-L1 upregulation caused by autophagy inhibition.","method":"Pharmacological autophagy inhibition, siRNA knockdown, Western blot, flow cytometry, NF-κB inhibition, xenograft experiments","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple knockdowns and pharmacological approaches; single lab with orthogonal methods","pmids":["30925913"],"is_preprint":false},{"year":2017,"finding":"Tumor-derived exosomes containing noncoding Y RNA hY4 induce PD-L1 expression in monocytes through TLR7 signaling; TLR7-deficient monocytes do not upregulate PD-L1 in response to CLL-derived exosomes or hY4 transfer.","method":"RNA sequencing and proteomics of CLL exosomes, transfer of exosomes/hY4 to monocytes, TLR7-knockout monocytes, pharmacological TLR inhibition","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic (TLR7 KO) and pharmacological validation of mechanism; multiple orthogonal approaches in a single rigorous study","pmids":["28754746"],"is_preprint":false},{"year":2019,"finding":"PD-L1 signaling through its intracellular domain delivers pro-survival and stress-resistance signals to cancer cells, functioning as an oncogenic signalosome independent of its immunosuppressive role as a PD-1 ligand.","method":"Review/mechanistic synthesis citing functional mutagenesis and downstream signaling pathway studies","journal":"Signal transduction and targeted therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review article summarizing findings; no new primary experimental data described in abstract","pmids":["30275987"],"is_preprint":false},{"year":2019,"finding":"Nonclassical monocytes (NCMs) constitutively express PD-L1 and use this PD-L1 to exert immunomodulatory function by promoting T-cell apoptosis within tertiary lymphoid organs; conversion of classical monocytes to NCMs requires contact with endosteal vessels.","method":"Two-photon microscopy, flow cytometry, bone marrow vasculature imaging, PD-L1+ NCM functional T-cell apoptosis assays in TLOs","journal":"Science immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging and functional assays; single lab with multiple methods","pmids":["31227596"],"is_preprint":false},{"year":2022,"finding":"PD-L1 is phosphorylated by casein kinase 2 (CK2) at Thr285 and Thr290, disrupting PD-L1 binding to SPOP (adaptor of CUL3 ubiquitin E3 ligase), thereby protecting PD-L1 from CUL3-mediated proteasomal degradation and stabilizing it; CK2 inhibition decreases PD-L1 levels, releases CD80 on dendritic cells, and reactivates T-cell function.","method":"In vitro kinase assays, Co-immunoprecipitation, site-directed mutagenesis, ubiquitination assays, CK2 inhibitor treatment, dendritic cell functional assays, syngeneic mouse model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay with mutagenesis, Co-IP, and in vivo validation; multiple orthogonal methods in single study","pmids":["35385574"],"is_preprint":false},{"year":2022,"finding":"PD-1/PD-L1 signaling regulates T cell lymphatic transendothelial migration: activated Tregs use PD-1/PD-L1 and activated CD4 Teffs use CD80/PD-L1 to cross lymphatic endothelial cells (LECs); PD-1/PD-L1 signals through PI3K/Akt and ERK to regulate VE-cadherin junctions, and through NFκB-p65 to upregulate VCAM-1 on LECs.","method":"Antibody blockade experiments, transendothelial migration assays in vitro and in vivo, signaling pathway inhibitors (PI3K/Akt, ERK, NFκB), VE-cadherin and VCAM-1 functional assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple pathway inhibitors and in vivo validation with defined signaling mechanisms; single lab with multiple orthogonal approaches","pmids":["35449134"],"is_preprint":false},{"year":2022,"finding":"Senescent cells upregulate PD-L1 in a manner dependent on the proinflammatory SASP program and JAK-STAT signaling; secreted factors from senescent cells are sufficient to upregulate PD-L1 in non-senescent cells via JAK-STAT; rapamycin downregulates PD-L1 in senescent cells.","method":"Senescence induction, conditioned media transfer, JAK-STAT inhibition, rapamycin treatment, Western blot, aged mouse tissue analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway inhibition and conditioned media experiments; single lab with multiple methods","pmids":["36154662"],"is_preprint":false},{"year":2023,"finding":"SGLT2 co-localizes with PD-L1 at the plasma membrane and recycling endosomes, preventing PD-L1 proteasome-mediated degradation; canagliflozin disrupts SGLT2-PD-L1 interaction, allowing recognition by Cullin3-SPOP E3 ligase leading to PD-L1 ubiquitination and proteasomal degradation.","method":"Co-localization imaging, Co-immunoprecipitation, ubiquitination assays, SGLT2 silencing, canagliflozin treatment, syngeneic and humanized mouse models","journal":"Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assays, genetic silencing, and in vivo validation; multiple orthogonal methods in single study","pmids":["36594471"],"is_preprint":false},{"year":2020,"finding":"eEF2K (an atypical protein kinase) promotes translation of PD-L1 mRNA by attenuating the inhibitory effect of an upstream open reading frame (uORF) with a non-canonical CUG start codon in the PD-L1 5'-UTR; eEF2K ablation reduces PD-L1 protein levels and increases cancer cell vulnerability to NK cell killing.","method":"eEF2K knockdown/knockout, polyribosome profiling, uORF reporter assays, NK cell cytotoxicity assays","journal":"Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — polyribosome profiling demonstrating direct translational regulation plus functional uORF analysis; multiple orthogonal methods","pmids":["33094805"],"is_preprint":false},{"year":2024,"finding":"PD-L1 directly interacts with MAP1LC3B (LC3) and localizes to phagosomes; baicalein potentiates the CD274-LC3 interaction to facilitate autophagic-lysosomal degradation of PD-L1, boosting T-cell-mediated antitumor immunity.","method":"Co-immunoprecipitation, bimolecular fluorescence complementation (BiFC), microscale thermophoresis, surface plasmon resonance, autophagy flux assays, mouse tumor models","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assays (MST, SPR) plus Co-IP and in vivo validation; single lab","pmids":["39710370"],"is_preprint":false},{"year":2024,"finding":"PD-L1 specifically enriches in phagosomes containing yeast (but not bacteria) and directly binds to yeast; the fungal ribosomal protein Rpl20b was identified as a PD-L1 ligand; PD-L1-dependent detection of Rpl20b cross-regulates IL-10 production induced by other innate immune receptors.","method":"Proximity labeling of phagosomal contents (PhagoPL), surface display library screening to identify fungal ligand, auxin-inducible PD-L1 depletion system, cytokine measurement","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — unbiased phagosome proteomics, surface display library screen, and genetic depletion with functional readout; multiple orthogonal methods in single rigorous study","pmids":["38839956"],"is_preprint":false},{"year":2024,"finding":"TRAF6 stabilizes YAP1 through K63-linked poly-ubiquitination, promoting formation of a YAP1/TFCP2 transcriptional complex that drives PD-L1 transcription in melanoma; TRAF6 suppression reduces membrane PD-L1 and enhances CD8+ T-cell cytolytic activity.","method":"CRISPR interference screening, Co-immunoprecipitation, K63-ubiquitination assays, transcription factor binding assays, in vitro and in vivo tumor models, flow cytometry","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen, Co-IP ubiquitination assays, and in vivo validation; single lab","pmids":["38583649"],"is_preprint":false},{"year":2018,"finding":"PD-L1 constitutively expressed on corneal epithelial cells negatively regulates innate immune clearance of HSV-1: B7-H1-deficient mice show increased chemokine expression, enhanced monocyte/macrophage infiltration, and decreased corneal HSV-1 titers; bone marrow chimera experiments demonstrate the effect is from non-hematopoietic (corneal) PD-L1.","method":"B7-H1 knockout mice, local antibody blockade, bone marrow chimera experiments, viral titer measurement, flow cytometry","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO plus bone marrow chimera epistasis plus local blockade; multiple orthogonal methods defining cellular source","pmids":["29669784"],"is_preprint":false}],"current_model":"CD274 (PD-L1/B7-H1) is a type I transmembrane B7-family ligand that binds PD-1 (and CD80) on T cells to deliver coinhibitory signals inducing T-cell apoptosis and functional exhaustion; its protein stability is controlled post-translationally by multiple E3 ligase complexes (CUL3-SPOP, CUL3-SPOP protected by CK2 phosphorylation at Thr285/290, and protected by CMTM6/4 and SGLT2 interactions that reduce ubiquitination), its transcription is directly driven by MYC (via promoter binding) and NF-κB, its translation is regulated by eEF2K acting on a 5'-UTR uORF, and it can be degraded via autophagy-lysosomal pathways through direct LC3 interaction; beyond T-cell suppression, PD-L1 delivers intrinsic intracellular survival signals in cancer cells, promotes EMT, regulates T-cell transendothelial migration through PI3K/Akt-ERK-NFκB signaling in lymphatic endothelium, functions as an innate receptor for fungal pathogens (binding yeast Rpl20b in phagosomes), and controls intestinal and corneal immune homeostasis through actions on innate immune cells."},"narrative":{"mechanistic_narrative":"CD274 (PD-L1/B7-H1) is a B7-family transmembrane ligand that delivers coinhibitory signals to T cells, originally identified as a third B7 member that co-stimulates T-cell proliferation and IL-10 secretion without binding CD28, CTLA-4, or ICOS [PMID:10581077], and subsequently shown to bind PD-1 on activated lymphocytes to induce T-cell apoptosis and cell-cycle arrest while also engaging a PD-1-independent receptor [PMID:12091876, PMID:12721664]. Beyond lymphocyte suppression, PD-L1 controls innate immune homeostasis: epithelial/parenchymal PD-L1 dampens intestinal inflammation by suppressing TNF-α and inducing IL-22 [PMID:24529703] and restrains innate clearance of corneal HSV-1 [PMID:29669784], and PD-L1 acts as a phagosomal innate sensor that directly binds the fungal ribosomal protein Rpl20b to cross-regulate IL-10 production [PMID:38839956]. Its expression is driven transcriptionally by direct MYC promoter binding [PMID:26966191] and by NF-κB-dependent and JAK-STAT-dependent inputs from TNF-α, autophagy blockade, senescence, and a TRAF6–YAP1/TFCP2 axis [PMID:27866850, PMID:30925913, PMID:36154662, PMID:38583649], with the PI3K/AKT pathway elevating PD-L1 upon PTEN loss [PMID:24764583]. Translation is gated by eEF2K relieving an inhibitory uORF in the PD-L1 5'-UTR [PMID:33094805]. PD-L1 protein abundance is set post-translationally by competing ubiquitination machinery: CK2 phosphorylation at Thr285/Thr290 blocks the CUL3-SPOP adaptor [PMID:35385574], CMTM6/CMTM4 [PMID:28813410], CSN5 deubiquitination [PMID:27866850], and SGLT2 sequestration at the membrane and recycling endosomes [PMID:36594471] each stabilize PD-L1, while direct LC3 (MAP1LC3B) binding routes it to autophagic-lysosomal degradation [PMID:39710370]. PD-L1 additionally exerts tumor-cell-intrinsic effects, promoting EMT in keratinocyte carcinogenesis [PMID:21730022].","teleology":[{"year":1999,"claim":"Established CD274 as a novel B7-family ligand distinct from known CD28-superfamily interactions, defining a previously unrecognized T-cell costimulatory axis.","evidence":"Receptor binding assays and T-cell co-stimulation with cytokine measurement","pmids":["10581077"],"confidence":"High","gaps":["Receptor identity not resolved","Costimulation vs coinhibition not reconciled"]},{"year":2002,"claim":"Showed tumor PD-L1 drives antigen-specific T-cell apoptosis and IFN-γ-inducible surface expression, framing it as an immune-evasion mechanism and therapeutic target.","evidence":"In vitro T-cell apoptosis assays, mouse P815 tumor model, IHC on human tumors","pmids":["12091876"],"confidence":"High","gaps":["Apoptotic receptor other than PD-1 not identified","Intracellular signaling not defined"]},{"year":2003,"claim":"Synthesized PD-1 as the inhibitory receptor for PD-L1 inducing apoptosis and cell-cycle arrest, while noting a distinct costimulatory receptor.","evidence":"Review of receptor binding and T-cell functional/apoptosis data","pmids":["12721664"],"confidence":"Medium","gaps":["Review, not primary data","Second receptor unidentified"]},{"year":2005,"claim":"Linked PD-L1 expression to oxygen tension in trophoblasts, indicating environmental/microenvironmental control of CD274 during placental development.","evidence":"Placental lysate immunoblot and trophoblast culture under varying oxygen with mRNA quantification","pmids":["16251499"],"confidence":"Medium","gaps":["Molecular oxygen-sensing pathway not mapped","Functional consequence for fetal tolerance not tested"]},{"year":2011,"claim":"Revealed a tumor-cell-intrinsic role beyond immune suppression: PD-L1 promotes EMT during squamous carcinogenesis.","evidence":"B7-H1 transgenic mouse chemical carcinogenesis with E-cadherin/Slug/Twist immunostaining","pmids":["21730022"],"confidence":"Medium","gaps":["Intracellular signaling driving EMT not defined","Single transgenic model"]},{"year":2014,"claim":"Defined PI3K/AKT signaling (via PTEN loss) and parenchymal PD-L1 in tissue immune homeostasis as distinct regulatory and effector contexts.","evidence":"PTEN knockdown with PI3K inhibitors and co-culture; DSS/TNBS colitis in B7-H1 KO and bone marrow chimeras","pmids":["24764583","24529703"],"confidence":"High","gaps":["Direct transcription factor downstream of AKT not pinned","Mechanism of IL-22 induction unresolved"]},{"year":2016,"claim":"Identified direct transcriptional (MYC) and post-translational deubiquitination (CSN5/NF-κB) control of PD-L1, separating its induction from its protein stability.","evidence":"MYC ChIP and genetic inactivation/rescue in mouse tumors; reciprocal Co-IP and ubiquitination assays for CSN5 with curcumin","pmids":["26966191","27866850"],"confidence":"High","gaps":["Cooperation of MYC with other TFs unclear","CSN5 specificity vs other DUBs not addressed"]},{"year":2017,"claim":"Established CMTM6/CMTM4 as surface partners that protect PD-L1 from ubiquitination, and an exosomal hY4/TLR7 route inducing PD-L1 in monocytes, defining stability and trans-cellular induction mechanisms.","evidence":"Haploid genetic screen, Co-IP, half-life assays (CMTM6); CLL exosome/hY4 transfer to TLR7-KO monocytes","pmids":["28813410","28754746"],"confidence":"High","gaps":["E3 ligase opposed by CMTM6 not fully resolved here","TLR7 downstream effectors driving PD-L1 not detailed"]},{"year":2018,"claim":"Demonstrated constitutive corneal PD-L1 restrains innate antiviral clearance, extending PD-L1 function to non-hematopoietic innate immune regulation.","evidence":"B7-H1 KO mice, local antibody blockade, bone marrow chimeras, HSV-1 titer measurement","pmids":["29669784"],"confidence":"High","gaps":["Receptor on innate cells unidentified","Signaling for chemokine suppression unclear"]},{"year":2019,"claim":"Extended PD-L1 biology to autophagy-coupled NF-κB induction, constitutive nonclassical monocyte expression, and a tumor-intrinsic survival signalosome.","evidence":"Autophagy inhibition with p62/NF-κB knockdowns; two-photon imaging of NCMs; mechanistic review of intracellular signaling","pmids":["30925913","31227596","30275987"],"confidence":"Medium","gaps":["Intracellular-domain signaling partners not biochemically defined (review)","NCM PD-L1 receptor engagement unmapped"]},{"year":2020,"claim":"Identified translational control of PD-L1 via eEF2K relieving a uORF, adding a layer between mRNA abundance and protein output.","evidence":"eEF2K knockdown/KO, polyribosome profiling, uORF reporter and NK cytotoxicity assays","pmids":["33094805"],"confidence":"High","gaps":["Signals controlling eEF2K activity on this uORF not defined","Generality across cell types untested"]},{"year":2022,"claim":"Resolved competing stability switches and a transendothelial migration function: CK2 phosphorylation blocks SPOP-mediated degradation, senescence/JAK-STAT induces PD-L1, and PD-1/PD-L1 signals through PI3K/Akt-ERK-NFκB in lymphatic endothelium.","evidence":"Kinase/mutagenesis/ubiquitination assays (CK2); senescence conditioned media with JAK-STAT inhibition; transendothelial migration assays with pathway inhibitors","pmids":["35385574","36154662","35449134"],"confidence":"High","gaps":["Upstream control of CK2 at PD-L1 unclear","LEC junctional signaling directionality incompletely mapped"]},{"year":2023,"claim":"Defined SGLT2 as a membrane/recycling-endosome partner shielding PD-L1 from CUL3-SPOP, providing a metabolically targetable stability mechanism.","evidence":"Co-localization imaging, Co-IP, ubiquitination assays, SGLT2 silencing, canagliflozin in syngeneic/humanized mice","pmids":["36594471"],"confidence":"High","gaps":["Whether SGLT2 transport activity is required not separated from binding","Tissue specificity of this axis unclear"]},{"year":2024,"claim":"Established new degradation and innate-sensing functions: direct LC3 binding routes PD-L1 to autophagy-lysosome, TRAF6-YAP1/TFCP2 drives transcription, and PD-L1 acts as a phagosomal fungal sensor binding Rpl20b.","evidence":"Co-IP/BiFC/MST/SPR autophagy assays; CRISPRi and K63-ubiquitination assays; PhagoPL proximity labeling and surface display screen with auxin-inducible depletion","pmids":["39710370","38583649","38839956"],"confidence":"Medium","gaps":["Physiological trigger for LC3-mediated turnover unclear","Signaling output of Rpl20b sensing beyond IL-10 cross-regulation undefined"]},{"year":null,"claim":"The intracellular signaling machinery that transduces PD-L1's tumor-cell-intrinsic survival and innate-sensing signals, and the identity of the non-PD-1 costimulatory/apoptotic receptor, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No biochemically defined intracellular-domain effectors","Second receptor still unidentified","Integration of competing stability pathways in vivo unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[12,15,20]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,6,17]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[17]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[19,20]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,8,20,22]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,6,14,17,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,21]}],"complexes":[],"partners":["PDCD1","CMTM6","CMTM4","SPOP","CSN5","SGLT2","MAP1LC3B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NZQ7","full_name":"Programmed cell death 1 ligand 1","aliases":["B7 homolog 1","B7-H1"],"length_aa":290,"mass_kda":33.3,"function":"Plays a critical role in induction and maintenance of immune tolerance to self (PubMed:11015443, PubMed:28813410, PubMed:28813417, PubMed:31399419). As a ligand for the inhibitory receptor PDCD1/PD-1, modulates the activation threshold of T-cells and limits T-cell effector response (PubMed:11015443, PubMed:28813410, PubMed:28813417, PubMed:36727298). Through a yet unknown activating receptor, may costimulate T-cell subsets that predominantly produce interleukin-10 (IL10) (PubMed:10581077). Can also act as a transcription coactivator: in response to hypoxia, translocates into the nucleus via its interaction with phosphorylated STAT3 and promotes transcription of GSDMC, leading to pyroptosis (PubMed:32929201) The PDCD1-mediated inhibitory pathway is exploited by tumors to attenuate anti-tumor immunity and escape destruction by the immune system, thereby facilitating tumor survival (PubMed:28813410, PubMed:28813417). The interaction with PDCD1/PD-1 inhibits cytotoxic T lymphocytes (CTLs) effector function (By similarity). The blockage of the PDCD1-mediated pathway results in the reversal of the exhausted T-cell phenotype and the normalization of the anti-tumor response, providing a rationale for cancer immunotherapy (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9NZQ7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD274","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD274","total_profiled":1310},"omim":[{"mim_id":"621526","title":"GLUTAMINYL-PEPTIDE CYCLOTRANSFERASE-LIKE PROTEIN; QPCTL","url":"https://www.omim.org/entry/621526"},{"mim_id":"621235","title":"AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 5; 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European Academy of Otology and Neurotology","url":"https://pubmed.ncbi.nlm.nih.gov/20601920","citation_count":28,"is_preprint":false},{"pmid":"14686489","id":"PMC_14686489","title":"Immunology of B7-H1 and its roles in human diseases.","date":"2003","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/14686489","citation_count":28,"is_preprint":false},{"pmid":"31724072","id":"PMC_31724072","title":"PD-L1 expression in gastroesophageal dysplastic lesions.","date":"2019","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31724072","citation_count":27,"is_preprint":false},{"pmid":"37290119","id":"PMC_37290119","title":"Regulation of PD-L1 Trafficking from Synthesis to Degradation.","date":"2023","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/37290119","citation_count":27,"is_preprint":false},{"pmid":"39710370","id":"PMC_39710370","title":"Baicalein tethers CD274/PD-L1 for autophagic degradation to boost antitumor immunity.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/39710370","citation_count":25,"is_preprint":false},{"pmid":"38583649","id":"PMC_38583649","title":"TRAF6 enhances PD-L1 expression through YAP1-TFCP2 signaling in melanoma.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/38583649","citation_count":25,"is_preprint":false},{"pmid":"29669784","id":"PMC_29669784","title":"PD-L1/B7-H1 Inhibits Viral Clearance by Macrophages in HSV-1-Infected Corneas.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/29669784","citation_count":25,"is_preprint":false},{"pmid":"39822174","id":"PMC_39822174","title":"PD-L1 as a Biomarker in Gastric Cancer Immunotherapy.","date":"2025","source":"Journal of gastric cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39822174","citation_count":24,"is_preprint":false},{"pmid":"30153998","id":"PMC_30153998","title":"PD-L1 expression in meningiomas.","date":"2018","source":"Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia","url":"https://pubmed.ncbi.nlm.nih.gov/30153998","citation_count":23,"is_preprint":false},{"pmid":"30190888","id":"PMC_30190888","title":"PD-L1 in melanoma: facts and myths.","date":"2016","source":"Melanoma management","url":"https://pubmed.ncbi.nlm.nih.gov/30190888","citation_count":22,"is_preprint":false},{"pmid":"29449680","id":"PMC_29449680","title":"PD-L1 expression in inflammatory myofibroblastic tumors.","date":"2018","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/29449680","citation_count":22,"is_preprint":false},{"pmid":"32416456","id":"PMC_32416456","title":"How microRNAs affect the PD-L1 and its synthetic pathway in cancer.","date":"2020","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32416456","citation_count":22,"is_preprint":false},{"pmid":"30680705","id":"PMC_30680705","title":"Nuclear localization of PD-L1: artifact or reality?","date":"2019","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/30680705","citation_count":22,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47161,"output_tokens":5760,"usd":0.113942,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14271,"output_tokens":4590,"usd":0.093052,"stage2_stop_reason":"end_turn"},"total_usd":0.206994,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"B7-H1 (CD274/PD-L1) was identified as a third B7 family member that does not bind CD28, CTLA-4, or ICOS, but co-stimulates T-cell proliferation and preferentially induces IL-10 secretion; IL-2 was required for this co-stimulatory effect.\",\n      \"method\": \"Receptor binding assays (negative for CD28/CTLA-4/ICOS), T-cell co-stimulation assays with polyclonal and allogeneic stimuli, cytokine measurement\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — original identification paper with multiple functional assays; foundational study replicated by numerous subsequent labs\",\n      \"pmids\": [\"10581077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Tumor-associated B7-H1 (PD-L1) promotes apoptosis of antigen-specific T cells in vitro and in vivo, increasing growth of immunogenic tumors; IFN-γ upregulates B7-H1 on tumor cell surfaces; the apoptotic effect is mediated largely by receptor(s) other than PD-1.\",\n      \"method\": \"In vitro T-cell apoptosis assays with human T-cell clones, mouse P815 tumor model in vivo, immunohistochemistry on human tumor tissues, flow cytometry\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vitro and in vivo), widely replicated; seminal functional study\",\n      \"pmids\": [\"12091876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"B7-H1 binds PD-1 on activated T and B cells, inhibiting T-cell responses by inducing apoptosis and arresting cell-cycle progression; it also has a costimulatory receptor distinct from PD-1 that drives IL-10 and IFN-γ production.\",\n      \"method\": \"Receptor binding studies, T-cell functional assays, apoptosis assays\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — review synthesizing prior experimental data; findings supported by multiple earlier studies but this paper itself is a review\",\n      \"pmids\": [\"12721664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTEN loss increases PD-L1 cell-surface expression and mRNA levels in breast cancer cells via PI3K/AKT signaling; AKT inhibitor MK-2206 or rapamycin reduces PD-L1 expression; increased PD-L1 from PTEN loss leads to decreased T-cell proliferation and increased T-cell apoptosis in co-culture.\",\n      \"method\": \"PTEN shRNA knockdown in stable cell lines, flow cytometry, Western blot, PI3K pathway inhibitor treatment (MK-2206, rapamycin), T-cell co-culture assays\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KD, pharmacological inhibition, functional co-culture) in single lab\",\n      \"pmids\": [\"24764583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MYC oncogene directly binds the promoter of the Pd-l1 (Cd274) gene to transcriptionally activate PD-L1 expression; MYC inactivation in mouse tumors downregulates PD-L1 and enhances antitumor immune response; forced PD-L1 expression during MYC inactivation suppresses immune response and tumor regression.\",\n      \"method\": \"ChIP (MYC binding to Cd274 promoter), genetic MYC inactivation in mouse tumor models, enforced PD-L1 expression rescue experiments, mRNA/protein measurements\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP demonstrating direct promoter binding plus genetic epistasis in vivo; multiple orthogonal methods\",\n      \"pmids\": [\"26966191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CSN5 (COP9 signalosome 5), induced by NF-κB p65 downstream of TNF-α signaling, deubiquitinates and stabilizes PD-L1, preventing its proteasomal degradation; curcumin inhibits CSN5 and reduces PD-L1 expression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, NF-κB inhibition, CSN5 knockdown/overexpression, Western blot, pharmacological inhibition with curcumin\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assays, and pharmacological rescue in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27866850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CMTM6 (and its closest family member CMTM4, but not other CMTM members) associates with PD-L1 protein at the cell surface, reduces PD-L1 ubiquitination, and increases PD-L1 protein half-life without affecting CD274 transcription, thereby enhancing PD-L1-mediated T-cell inhibition.\",\n      \"method\": \"Haploid genetic screen, haploid genetic modifier screen, genetic complementation, Co-immunoprecipitation, ubiquitination assays, protein half-life measurements, T-cell inhibition assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — unbiased genetic screen + reciprocal Co-IP + functional validation; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"28813410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PD-L1 (CD274) expression in trophoblast cells is regulated by oxygen concentration: low oxygen rapidly downregulates CD274 mRNA (within 4-12 h), and protein levels increase with rising oxygen concentrations, paralleling in vivo expression patterns during placental development.\",\n      \"method\": \"Immunoblot of first- and second-trimester placental lysates, trophoblast cell culture under varying oxygen concentrations, mRNA quantification\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct experimental manipulation of oxygen with mRNA and protein measurements; single lab, two methods\",\n      \"pmids\": [\"16251499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Intestinal epithelium-expressed B7-H1 (PD-L1) controls intestinal inflammation independently of adaptive immunity; using bone marrow chimeric and knockout mice, parenchymal (non-hematopoietic) B7-H1 dampens inflammation by inhibiting TNF-α production and stimulating IL-22 secretion from CD11c+CD11b+ lamina propria cells.\",\n      \"method\": \"DSS/TNBS-induced colitis models, B7-H1 knockout mice, bone marrow chimera experiments, cytokine measurement\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular and cytokine phenotype, epistasis via bone marrow chimeras; multiple orthogonal methods\",\n      \"pmids\": [\"24529703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"B7-H1 (PD-L1) overexpression in keratinocytes accelerates chemically induced squamous cell carcinoma by promoting epithelial-mesenchymal transition (EMT), as evidenced by reduced E-cadherin and elevated Slug/Twist transcription factors in B7-H1 transgenic mouse-derived keratinocytes and SCCs.\",\n      \"method\": \"B7-H1 transgenic mouse model, chemical carcinogenesis model, immunostaining for E-cadherin, Slug, and Twist\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse model with defined molecular markers of EMT; single lab\",\n      \"pmids\": [\"21730022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Autophagy inhibition increases PD-L1 expression in gastric cancer cells through accumulation of p62/SQSTM1 and consequent NF-κB activation; NF-κB inhibition or p62/SQSTM1 knockdown attenuates PD-L1 upregulation caused by autophagy inhibition.\",\n      \"method\": \"Pharmacological autophagy inhibition, siRNA knockdown, Western blot, flow cytometry, NF-κB inhibition, xenograft experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple knockdowns and pharmacological approaches; single lab with orthogonal methods\",\n      \"pmids\": [\"30925913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Tumor-derived exosomes containing noncoding Y RNA hY4 induce PD-L1 expression in monocytes through TLR7 signaling; TLR7-deficient monocytes do not upregulate PD-L1 in response to CLL-derived exosomes or hY4 transfer.\",\n      \"method\": \"RNA sequencing and proteomics of CLL exosomes, transfer of exosomes/hY4 to monocytes, TLR7-knockout monocytes, pharmacological TLR inhibition\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (TLR7 KO) and pharmacological validation of mechanism; multiple orthogonal approaches in a single rigorous study\",\n      \"pmids\": [\"28754746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PD-L1 signaling through its intracellular domain delivers pro-survival and stress-resistance signals to cancer cells, functioning as an oncogenic signalosome independent of its immunosuppressive role as a PD-1 ligand.\",\n      \"method\": \"Review/mechanistic synthesis citing functional mutagenesis and downstream signaling pathway studies\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review article summarizing findings; no new primary experimental data described in abstract\",\n      \"pmids\": [\"30275987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nonclassical monocytes (NCMs) constitutively express PD-L1 and use this PD-L1 to exert immunomodulatory function by promoting T-cell apoptosis within tertiary lymphoid organs; conversion of classical monocytes to NCMs requires contact with endosteal vessels.\",\n      \"method\": \"Two-photon microscopy, flow cytometry, bone marrow vasculature imaging, PD-L1+ NCM functional T-cell apoptosis assays in TLOs\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging and functional assays; single lab with multiple methods\",\n      \"pmids\": [\"31227596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PD-L1 is phosphorylated by casein kinase 2 (CK2) at Thr285 and Thr290, disrupting PD-L1 binding to SPOP (adaptor of CUL3 ubiquitin E3 ligase), thereby protecting PD-L1 from CUL3-mediated proteasomal degradation and stabilizing it; CK2 inhibition decreases PD-L1 levels, releases CD80 on dendritic cells, and reactivates T-cell function.\",\n      \"method\": \"In vitro kinase assays, Co-immunoprecipitation, site-directed mutagenesis, ubiquitination assays, CK2 inhibitor treatment, dendritic cell functional assays, syngeneic mouse model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay with mutagenesis, Co-IP, and in vivo validation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"35385574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PD-1/PD-L1 signaling regulates T cell lymphatic transendothelial migration: activated Tregs use PD-1/PD-L1 and activated CD4 Teffs use CD80/PD-L1 to cross lymphatic endothelial cells (LECs); PD-1/PD-L1 signals through PI3K/Akt and ERK to regulate VE-cadherin junctions, and through NFκB-p65 to upregulate VCAM-1 on LECs.\",\n      \"method\": \"Antibody blockade experiments, transendothelial migration assays in vitro and in vivo, signaling pathway inhibitors (PI3K/Akt, ERK, NFκB), VE-cadherin and VCAM-1 functional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway inhibitors and in vivo validation with defined signaling mechanisms; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"35449134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Senescent cells upregulate PD-L1 in a manner dependent on the proinflammatory SASP program and JAK-STAT signaling; secreted factors from senescent cells are sufficient to upregulate PD-L1 in non-senescent cells via JAK-STAT; rapamycin downregulates PD-L1 in senescent cells.\",\n      \"method\": \"Senescence induction, conditioned media transfer, JAK-STAT inhibition, rapamycin treatment, Western blot, aged mouse tissue analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway inhibition and conditioned media experiments; single lab with multiple methods\",\n      \"pmids\": [\"36154662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SGLT2 co-localizes with PD-L1 at the plasma membrane and recycling endosomes, preventing PD-L1 proteasome-mediated degradation; canagliflozin disrupts SGLT2-PD-L1 interaction, allowing recognition by Cullin3-SPOP E3 ligase leading to PD-L1 ubiquitination and proteasomal degradation.\",\n      \"method\": \"Co-localization imaging, Co-immunoprecipitation, ubiquitination assays, SGLT2 silencing, canagliflozin treatment, syngeneic and humanized mouse models\",\n      \"journal\": \"Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assays, genetic silencing, and in vivo validation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"36594471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"eEF2K (an atypical protein kinase) promotes translation of PD-L1 mRNA by attenuating the inhibitory effect of an upstream open reading frame (uORF) with a non-canonical CUG start codon in the PD-L1 5'-UTR; eEF2K ablation reduces PD-L1 protein levels and increases cancer cell vulnerability to NK cell killing.\",\n      \"method\": \"eEF2K knockdown/knockout, polyribosome profiling, uORF reporter assays, NK cell cytotoxicity assays\",\n      \"journal\": \"Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — polyribosome profiling demonstrating direct translational regulation plus functional uORF analysis; multiple orthogonal methods\",\n      \"pmids\": [\"33094805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PD-L1 directly interacts with MAP1LC3B (LC3) and localizes to phagosomes; baicalein potentiates the CD274-LC3 interaction to facilitate autophagic-lysosomal degradation of PD-L1, boosting T-cell-mediated antitumor immunity.\",\n      \"method\": \"Co-immunoprecipitation, bimolecular fluorescence complementation (BiFC), microscale thermophoresis, surface plasmon resonance, autophagy flux assays, mouse tumor models\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assays (MST, SPR) plus Co-IP and in vivo validation; single lab\",\n      \"pmids\": [\"39710370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PD-L1 specifically enriches in phagosomes containing yeast (but not bacteria) and directly binds to yeast; the fungal ribosomal protein Rpl20b was identified as a PD-L1 ligand; PD-L1-dependent detection of Rpl20b cross-regulates IL-10 production induced by other innate immune receptors.\",\n      \"method\": \"Proximity labeling of phagosomal contents (PhagoPL), surface display library screening to identify fungal ligand, auxin-inducible PD-L1 depletion system, cytokine measurement\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — unbiased phagosome proteomics, surface display library screen, and genetic depletion with functional readout; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"38839956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRAF6 stabilizes YAP1 through K63-linked poly-ubiquitination, promoting formation of a YAP1/TFCP2 transcriptional complex that drives PD-L1 transcription in melanoma; TRAF6 suppression reduces membrane PD-L1 and enhances CD8+ T-cell cytolytic activity.\",\n      \"method\": \"CRISPR interference screening, Co-immunoprecipitation, K63-ubiquitination assays, transcription factor binding assays, in vitro and in vivo tumor models, flow cytometry\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen, Co-IP ubiquitination assays, and in vivo validation; single lab\",\n      \"pmids\": [\"38583649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PD-L1 constitutively expressed on corneal epithelial cells negatively regulates innate immune clearance of HSV-1: B7-H1-deficient mice show increased chemokine expression, enhanced monocyte/macrophage infiltration, and decreased corneal HSV-1 titers; bone marrow chimera experiments demonstrate the effect is from non-hematopoietic (corneal) PD-L1.\",\n      \"method\": \"B7-H1 knockout mice, local antibody blockade, bone marrow chimera experiments, viral titer measurement, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus bone marrow chimera epistasis plus local blockade; multiple orthogonal methods defining cellular source\",\n      \"pmids\": [\"29669784\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD274 (PD-L1/B7-H1) is a type I transmembrane B7-family ligand that binds PD-1 (and CD80) on T cells to deliver coinhibitory signals inducing T-cell apoptosis and functional exhaustion; its protein stability is controlled post-translationally by multiple E3 ligase complexes (CUL3-SPOP, CUL3-SPOP protected by CK2 phosphorylation at Thr285/290, and protected by CMTM6/4 and SGLT2 interactions that reduce ubiquitination), its transcription is directly driven by MYC (via promoter binding) and NF-κB, its translation is regulated by eEF2K acting on a 5'-UTR uORF, and it can be degraded via autophagy-lysosomal pathways through direct LC3 interaction; beyond T-cell suppression, PD-L1 delivers intrinsic intracellular survival signals in cancer cells, promotes EMT, regulates T-cell transendothelial migration through PI3K/Akt-ERK-NFκB signaling in lymphatic endothelium, functions as an innate receptor for fungal pathogens (binding yeast Rpl20b in phagosomes), and controls intestinal and corneal immune homeostasis through actions on innate immune cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD274 (PD-L1/B7-H1) is a B7-family transmembrane ligand that delivers coinhibitory signals to T cells, originally identified as a third B7 member that co-stimulates T-cell proliferation and IL-10 secretion without binding CD28, CTLA-4, or ICOS [#0], and subsequently shown to bind PD-1 on activated lymphocytes to induce T-cell apoptosis and cell-cycle arrest while also engaging a PD-1-independent receptor [#1, #2]. Beyond lymphocyte suppression, PD-L1 controls innate immune homeostasis: epithelial/parenchymal PD-L1 dampens intestinal inflammation by suppressing TNF-\\u03b1 and inducing IL-22 [#8] and restrains innate clearance of corneal HSV-1 [#22], and PD-L1 acts as a phagosomal innate sensor that directly binds the fungal ribosomal protein Rpl20b to cross-regulate IL-10 production [#20]. Its expression is driven transcriptionally by direct MYC promoter binding [#4] and by NF-\\u03baB-dependent and JAK-STAT-dependent inputs from TNF-\\u03b1, autophagy blockade, senescence, and a TRAF6\\u2013YAP1/TFCP2 axis [#5, #10, #16, #21], with the PI3K/AKT pathway elevating PD-L1 upon PTEN loss [#3]. Translation is gated by eEF2K relieving an inhibitory uORF in the PD-L1 5'-UTR [#18]. PD-L1 protein abundance is set post-translationally by competing ubiquitination machinery: CK2 phosphorylation at Thr285/Thr290 blocks the CUL3-SPOP adaptor [#14], CMTM6/CMTM4 [#6], CSN5 deubiquitination [#5], and SGLT2 sequestration at the membrane and recycling endosomes [#17] each stabilize PD-L1, while direct LC3 (MAP1LC3B) binding routes it to autophagic-lysosomal degradation [#19]. PD-L1 additionally exerts tumor-cell-intrinsic effects, promoting EMT in keratinocyte carcinogenesis [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established CD274 as a novel B7-family ligand distinct from known CD28-superfamily interactions, defining a previously unrecognized T-cell costimulatory axis.\",\n      \"evidence\": \"Receptor binding assays and T-cell co-stimulation with cytokine measurement\",\n      \"pmids\": [\"10581077\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor identity not resolved\", \"Costimulation vs coinhibition not reconciled\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed tumor PD-L1 drives antigen-specific T-cell apoptosis and IFN-\\u03b3-inducible surface expression, framing it as an immune-evasion mechanism and therapeutic target.\",\n      \"evidence\": \"In vitro T-cell apoptosis assays, mouse P815 tumor model, IHC on human tumors\",\n      \"pmids\": [\"12091876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apoptotic receptor other than PD-1 not identified\", \"Intracellular signaling not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Synthesized PD-1 as the inhibitory receptor for PD-L1 inducing apoptosis and cell-cycle arrest, while noting a distinct costimulatory receptor.\",\n      \"evidence\": \"Review of receptor binding and T-cell functional/apoptosis data\",\n      \"pmids\": [\"12721664\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review, not primary data\", \"Second receptor unidentified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked PD-L1 expression to oxygen tension in trophoblasts, indicating environmental/microenvironmental control of CD274 during placental development.\",\n      \"evidence\": \"Placental lysate immunoblot and trophoblast culture under varying oxygen with mRNA quantification\",\n      \"pmids\": [\"16251499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular oxygen-sensing pathway not mapped\", \"Functional consequence for fetal tolerance not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a tumor-cell-intrinsic role beyond immune suppression: PD-L1 promotes EMT during squamous carcinogenesis.\",\n      \"evidence\": \"B7-H1 transgenic mouse chemical carcinogenesis with E-cadherin/Slug/Twist immunostaining\",\n      \"pmids\": [\"21730022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular signaling driving EMT not defined\", \"Single transgenic model\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined PI3K/AKT signaling (via PTEN loss) and parenchymal PD-L1 in tissue immune homeostasis as distinct regulatory and effector contexts.\",\n      \"evidence\": \"PTEN knockdown with PI3K inhibitors and co-culture; DSS/TNBS colitis in B7-H1 KO and bone marrow chimeras\",\n      \"pmids\": [\"24764583\", \"24529703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcription factor downstream of AKT not pinned\", \"Mechanism of IL-22 induction unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified direct transcriptional (MYC) and post-translational deubiquitination (CSN5/NF-\\u03baB) control of PD-L1, separating its induction from its protein stability.\",\n      \"evidence\": \"MYC ChIP and genetic inactivation/rescue in mouse tumors; reciprocal Co-IP and ubiquitination assays for CSN5 with curcumin\",\n      \"pmids\": [\"26966191\", \"27866850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cooperation of MYC with other TFs unclear\", \"CSN5 specificity vs other DUBs not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established CMTM6/CMTM4 as surface partners that protect PD-L1 from ubiquitination, and an exosomal hY4/TLR7 route inducing PD-L1 in monocytes, defining stability and trans-cellular induction mechanisms.\",\n      \"evidence\": \"Haploid genetic screen, Co-IP, half-life assays (CMTM6); CLL exosome/hY4 transfer to TLR7-KO monocytes\",\n      \"pmids\": [\"28813410\", \"28754746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase opposed by CMTM6 not fully resolved here\", \"TLR7 downstream effectors driving PD-L1 not detailed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated constitutive corneal PD-L1 restrains innate antiviral clearance, extending PD-L1 function to non-hematopoietic innate immune regulation.\",\n      \"evidence\": \"B7-H1 KO mice, local antibody blockade, bone marrow chimeras, HSV-1 titer measurement\",\n      \"pmids\": [\"29669784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor on innate cells unidentified\", \"Signaling for chemokine suppression unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended PD-L1 biology to autophagy-coupled NF-\\u03baB induction, constitutive nonclassical monocyte expression, and a tumor-intrinsic survival signalosome.\",\n      \"evidence\": \"Autophagy inhibition with p62/NF-\\u03baB knockdowns; two-photon imaging of NCMs; mechanistic review of intracellular signaling\",\n      \"pmids\": [\"30925913\", \"31227596\", \"30275987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular-domain signaling partners not biochemically defined (review)\", \"NCM PD-L1 receptor engagement unmapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified translational control of PD-L1 via eEF2K relieving a uORF, adding a layer between mRNA abundance and protein output.\",\n      \"evidence\": \"eEF2K knockdown/KO, polyribosome profiling, uORF reporter and NK cytotoxicity assays\",\n      \"pmids\": [\"33094805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling eEF2K activity on this uORF not defined\", \"Generality across cell types untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved competing stability switches and a transendothelial migration function: CK2 phosphorylation blocks SPOP-mediated degradation, senescence/JAK-STAT induces PD-L1, and PD-1/PD-L1 signals through PI3K/Akt-ERK-NF\\u03baB in lymphatic endothelium.\",\n      \"evidence\": \"Kinase/mutagenesis/ubiquitination assays (CK2); senescence conditioned media with JAK-STAT inhibition; transendothelial migration assays with pathway inhibitors\",\n      \"pmids\": [\"35385574\", \"36154662\", \"35449134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream control of CK2 at PD-L1 unclear\", \"LEC junctional signaling directionality incompletely mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined SGLT2 as a membrane/recycling-endosome partner shielding PD-L1 from CUL3-SPOP, providing a metabolically targetable stability mechanism.\",\n      \"evidence\": \"Co-localization imaging, Co-IP, ubiquitination assays, SGLT2 silencing, canagliflozin in syngeneic/humanized mice\",\n      \"pmids\": [\"36594471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SGLT2 transport activity is required not separated from binding\", \"Tissue specificity of this axis unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established new degradation and innate-sensing functions: direct LC3 binding routes PD-L1 to autophagy-lysosome, TRAF6-YAP1/TFCP2 drives transcription, and PD-L1 acts as a phagosomal fungal sensor binding Rpl20b.\",\n      \"evidence\": \"Co-IP/BiFC/MST/SPR autophagy assays; CRISPRi and K63-ubiquitination assays; PhagoPL proximity labeling and surface display screen with auxin-inducible depletion\",\n      \"pmids\": [\"39710370\", \"38583649\", \"38839956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological trigger for LC3-mediated turnover unclear\", \"Signaling output of Rpl20b sensing beyond IL-10 cross-regulation undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intracellular signaling machinery that transduces PD-L1's tumor-cell-intrinsic survival and innate-sensing signals, and the identity of the non-PD-1 costimulatory/apoptotic receptor, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No biochemically defined intracellular-domain effectors\", \"Second receptor still unidentified\", \"Integration of competing stability pathways in vivo unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [12, 15, 20]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 6, 17]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [19, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 8, 20, 22]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 6, 14, 17, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PDCD1\", \"CMTM6\", \"CMTM4\", \"SPOP\", \"CSN5\", \"SGLT2\", \"MAP1LC3B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}