{"gene":"HBZ","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2003,"finding":"HBZ dimerizes with JunB and c-Jun via bZIP domains, suppresses c-Jun-mediated AP-1 transcription by decreasing its DNA-binding activity, enhances JunB transcriptional activity, and inhibits c-Jun-mediated basal expression of the HTLV-1 promoter.","method":"Co-immunoprecipitation, cellular colocalization, reporter gene (luciferase) assays, DNA-binding assays in CEM cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus functional reporter assays, independently replicated in multiple subsequent studies","pmids":["12937177"],"is_preprint":false},{"year":2004,"finding":"HBZ interacts with JunD in vitro and in vivo via the bZIP domains of both proteins, and stimulates JunD-dependent transcription; the amino-terminus of HBZ is required for transcriptional activation.","method":"In vitro binding assay, co-immunoprecipitation, luciferase reporter assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vitro binding and functional assay, single lab","pmids":["15044019"],"is_preprint":false},{"year":2005,"finding":"HBZ suppresses AP-1 activity through a dual mechanism: (1) inhibiting c-Jun DNA-binding activity and (2) promoting proteasome-dependent degradation of c-Jun; both the N-terminal and leucine-zipper regions of HBZ are required for c-Jun elimination.","method":"Luciferase assays, Western blotting with proteasome inhibitor treatment, HBZ deletion mutant analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with deletion mutants and pharmacological inhibition, single lab","pmids":["15592508"],"is_preprint":false},{"year":2005,"finding":"HBZ nuclear targeting is mediated by three distinct nuclear localization signals (NLS); at least two NLS are necessary for nuclear translocation; wild-type HBZ accumulates in nuclear speckles (not Cajal bodies, splicing factor compartments, or PML bodies); the integrity of the full protein is required for speckle localization; immunogold EM localizes HBZ to heterochromatin.","method":"Deletion mutant analysis in mammalian cells, fluorescence microscopy, immunogold electron microscopy","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with deletion mutants and EM, single lab","pmids":["15755797"],"is_preprint":false},{"year":2006,"finding":"The DNA-binding domain of HBZ is responsible for its inhibitory effect on c-Jun trans-activation; a cluster of six charged amino acids adjacent to the DNA-contact region (a modified Fos-associated cluster) is critical for regulating Jun transcriptional potency, including HBZ's ability to stimulate JunD activity.","method":"HBZ/c-Fos chimera construction, reporter gene assays, mutagenesis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis with functional reporter readout, single lab","pmids":["16717281"],"is_preprint":false},{"year":2006,"finding":"A spliced isoform of HBZ (HBZ-SI/HBZ-SP1) localizes to distinct subnuclear structures (intense nuclear spots/HBZ-NBs and nucleoli) distinct from the unspliced HBZ isoform, indicating isoform-specific subnuclear targeting.","method":"RT-PCR, 5'/3' RACE, Western blotting, immunofluorescence microscopy","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by fluorescence microscopy with isoform-specific constructs, single lab","pmids":["16474156"],"is_preprint":false},{"year":2007,"finding":"HBZ-SP1 represses JunB transcriptional activity by sequestering JunB into HBZ nuclear bodies (HBZ-NBs); the ZIP domain of HBZ-SP1 is required for association with HBZ-NBs; JunB co-expression redistributes into HBZ-NBs whereas JunD co-expression results in diffuse nucleoplasmic distribution without NB formation.","method":"Fluorescence microscopy, FRAP, co-transfection/reporter assays in COS and HeLa cells","journal":"Retrovirology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP plus functional co-transfection assays, single lab","pmids":["17306025"],"is_preprint":false},{"year":2007,"finding":"HBZ cooperates with JunD to activate hTERT promoter transcription; HBZ/JunD heterodimers interact with Sp1 and activate hTERT transcription through GC-rich Sp1 binding sites in the proximal hTERT promoter; ChIP confirms HBZ and JunD co-occupy the proximal hTERT promoter region.","method":"Co-transfection luciferase assays, RT-PCR for hTERT transcripts, chromatin immunoprecipitation (ChIP)","journal":"Retrovirology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional reporter assays, single lab","pmids":["18078517"],"is_preprint":false},{"year":2008,"finding":"HBZ binds directly to the KIX domain of p300/CBP via two LXXLL-like motifs in its N-terminal activation domain; this interaction specifically targets the MLL-binding surface of KIX, competing with Tax for p300/CBP binding and inhibiting coactivator recruitment to the viral promoter — a second mechanism of HTLV-1 transcriptional repression distinct from CREB dimerization.","method":"Co-immunoprecipitation, in vitro binding/pulldown assays, luciferase reporter assays, mutagenesis of LXXLL-like motifs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding with mutagenesis plus functional reporter assays, replicated in subsequent structural study","pmids":["18599479"],"is_preprint":false},{"year":2008,"finding":"HBZ promotes ubiquitin-independent proteasomal degradation of c-Jun: HBZ directly interacts with both the 26S proteasome and c-Jun, acting as a tethering factor that delivers c-Jun to the proteasome without requiring polyubiquitination.","method":"Co-immunoprecipitation with the 26S proteasome, ubiquitination assays, proteasome inhibitor treatment, in vitro binding","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct biochemical reconstitution of proteasome-HBZ-c-Jun complex with ubiquitination assays and mutagenesis, single lab with multiple orthogonal methods","pmids":["18805793"],"is_preprint":false},{"year":2008,"finding":"The spliced HBZ (sHBZ) isoform shows stronger suppression of Tax-mediated transcriptional activation and promotes T-cell proliferation, while unspliced HBZ (usHBZ) does not promote proliferation; sHBZ transcription from a TATA-less promoter is driven by Sp1 sites and is upregulated by Tax via Tax-responsive elements in the 3' LTR.","method":"Luciferase promoter assays, Sp1 site mutagenesis, T-cell proliferation assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays comparing isoforms with promoter mutagenesis, single lab","pmids":["18653454"],"is_preprint":false},{"year":2009,"finding":"Repression of c-Jun transcriptional activity by HBZ-SP1 is predominantly due to sequestration of c-Jun into HBZ nuclear bodies rather than inhibition of DNA-binding activity; a DNA-binding-improved HBZ-SP1 chimera retains repressive activity through sequestration.","method":"Chimeric mutant construction, DNA-binding assays, fluorescence microscopy, reporter gene assays","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis with functional readout plus localization, single lab","pmids":["19595408"],"is_preprint":false},{"year":2010,"finding":"HBZ interacts with MafB via bZIP domains, abrogates MafB DNA-binding at Maf recognition elements (MARE), and promotes proteasomal degradation of MafB; identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation and luciferase assays.","method":"Yeast two-hybrid screen, co-immunoprecipitation, luciferase reporter assay, proteasome inhibitor treatment","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid discovery confirmed by Co-IP and functional assays, single lab","pmids":["20506502"],"is_preprint":false},{"year":2010,"finding":"HBZ interacts with MAFB and MAFG via its basic region in a coiled-coil array system; HBZ also forms heterodimers with ATF2, CEBPG, and CREBZF; all new interactions confirmed by circular dichroism in solution; HBZ-MAFB/MAFG heterocomplexes can associate with MARE-site DNA.","method":"Coiled-coil peptide arrays, circular dichroism spectroscopy, DNA-binding assays","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with two orthogonal biophysical methods, single lab","pmids":["20102225"],"is_preprint":false},{"year":2011,"finding":"HBZ down-regulates NF-κB activity induced by Tax, thereby alleviating Tax-induced cellular senescence driven by p21(CIP1/WAF1) and p27(KIP1); shRNA-mediated knockdown confirmed that HBZ delays or prevents the onset of Tax-induced senescence.","method":"shRNA knockdown, NF-κB reporter assays, senescence assays, cell proliferation assays","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown with defined functional phenotype (senescence), single lab","pmids":["21552325"],"is_preprint":false},{"year":2011,"finding":"HBZ binds to the KIX domain of p300/CBP via two φXXφφ motifs targeting the MLL-binding surface; this simultaneously inhibits MLL-mediated transcription and enhances c-Myb and CREB transcriptional activity by allosterically promoting their binding to the opposite KIX surface.","method":"In vitro binding assays, luciferase reporter assays, domain mutagenesis","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding domain mapping with functional assays, single lab","pmids":["21497608"],"is_preprint":false},{"year":2012,"finding":"HBZ directly inhibits the histone acetyltransferase (HAT) activity of p300/CBP through its bZIP domain, leading to reduced H3K18 acetylation in HBZ-expressing cells and in HTLV-1-infected cells; HBZ also inhibits acetylation of NF-κB p65 and p53.","method":"In vitro HAT activity assay, Western blotting for H3K18ac, comparison of HTLV-1-infected vs. uninfected cells","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with domain mutagenesis plus cellular validation, single lab with multiple orthogonal methods","pmids":["22434882"],"is_preprint":false},{"year":2013,"finding":"HBZ is exported from the nucleus to the cytoplasm via a CRM1-dependent nuclear export signal (NES) in its N-terminal region; in the cytoplasm, HBZ interacts with GADD34 (N-terminal region of HBZ binds C-terminal region of GADD34), activates mTOR signaling (increased S6 kinase phosphorylation), and suppresses starvation-induced autophagy.","method":"CRM1 inhibitor (leptomycin B) treatment, co-immunoprecipitation, domain mapping, phosphorylation assays, autophagy assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition of nuclear export plus Co-IP domain mapping and functional signaling assays, single lab","pmids":["23708656"],"is_preprint":false},{"year":2014,"finding":"HBZ inhibits Rex-mediated nuclear export of intron-containing (unspliced) viral mRNAs; shRNA-mediated knockdown of HBZ or overexpression of Rex reactivates viral structural protein expression, indicating HBZ maintains HTLV-1 latency partly by blocking Rex function.","method":"shRNA knockdown of HBZ, Rex overexpression, viral mRNA nuclear export assays, RT-PCR for viral transcripts","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown and overexpression with defined molecular phenotype, single lab","pmids":["24699669"],"is_preprint":false},{"year":2014,"finding":"HBZ activates BDNF expression in HTLV-1-infected T cells; elevated BDNF and its receptor TrkB are found in HTLV-1-infected T-cell lines; chemical inhibition of TrkB signaling increases apoptosis in HTLV-1-infected cells and reduces phosphorylation of GSK-3β, demonstrating a functional BDNF/TrkB autocrine/paracrine survival signaling loop promoted by HBZ.","method":"Ectopic HBZ expression, RT-PCR/Western blotting for BDNF and TrkB, TrkB chemical inhibitor treatment, apoptosis assays, phosphorylation assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ectopic expression plus pharmacological inhibition with defined functional phenotype, single lab","pmids":["25210182"],"is_preprint":false},{"year":2015,"finding":"Endogenous HBZ protein in HTLV-1-infected and ATL cells localizes in speckle-like nuclear structures; endogenous HBZ interacts with p300, JunD, and partially co-localizes with CBP and CREB2 in vivo; quantified at 17,000–40,000 molecules per cell (20–50-fold less than in overexpression systems).","method":"Monoclonal antibody immunofluorescence, confocal microscopy, co-immunoprecipitation with endogenous protein, single-molecule quantification","journal":"Retrovirology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous protein localization and Co-IP with validated monoclonal antibody, single lab","pmids":["26140924"],"is_preprint":false},{"year":2016,"finding":"HBZ represses p53 activity by directly inhibiting the HAT activity of p300/CBP (reducing p53 acetylation) and by binding to and inhibiting the HAT activity of HBO1 (a p53 coactivator at the p21/CDKN1A promoter), leading to impaired p53-dependent activation of p21/CDKN1A and GADD45A and delay in G2 arrest.","method":"Co-immunoprecipitation, in vitro HAT activity assay, luciferase/gene expression assays, cell cycle analysis in HCT116 p53+/+ cells","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay, Co-IP, and functional cellular assays with multiple orthogonal methods, single lab","pmids":["26625199"],"is_preprint":false},{"year":2016,"finding":"HBZ induces CCR4 expression in CD4+ T cells by activating GATA3, which in turn activates CCR4 promoter transcription; HBZ silencing in ATL cell lines inhibits CCR4 expression; in HBZ-transgenic mice, CD4+ T cells migrate preferentially and proliferate in response to CCR4 ligands CCL17/CCL22 and CD103 ligand E-cadherin.","method":"Ectopic HBZ expression, shRNA knockdown, promoter reporter assays, HBZ-transgenic mouse air-pouch migration model, CCR4 antagonist treatment","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mechanistic assays corroborated by transgenic mouse model with pharmacological inhibition, single lab","pmids":["27402079"],"is_preprint":false},{"year":2017,"finding":"HBZ induces expression of the ΔJunD isoform (N-terminal truncated, oncogenic) by causing nuclear retention of RPS25 mRNA and loss of RPS25 protein, a small ribosomal subunit component; loss of RPS25 bypasses translational control of the JunD upstream open reading frame (uORF), shifting translation initiation to produce ΔJunD, which promotes cell proliferation and transformation.","method":"Western blotting for JunD isoforms, qRT-PCR for RPS25 mRNA, ChIP for JunD promoter, cell proliferation and transformation assays, nuclear fractionation","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus biochemical fractionation and functional proliferation assays, single lab","pmids":["28260789"],"is_preprint":false},{"year":2017,"finding":"HBZ localizes exclusively in the cytoplasm of PBMCs from HAM/TSP patients; in ATL cell lines it localizes in the nucleus; HBZ and Tax-1 are rarely co-expressed in the same cell in HAM/TSP patients; cytoplasmic HBZ is found almost exclusively in CD4+ T cells.","method":"Immunofluorescence with validated monoclonal antibody 4D4-F3, confocal microscopy, PBMC fractionation and cell-type analysis","journal":"PLoS neglected tropical diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with validated antibody on primary patient cells, single lab; replicated in subsequent studies","pmids":["28095504"],"is_preprint":false},{"year":2017,"finding":"HBZ enhances IRF7-induced IFN-α and ISRE promoter activity and IFN-α production, and enhances IRF7 activation by TBK1/IKKε; conversely, HBZ cooperates with Tax to suppress IRF3-induced IFN-β; HBZ physically interacts with IRF7 and IKKε but not with IRF3 or TBK1.","method":"Co-immunoprecipitation, luciferase reporter assays, IFN-α ELISA, IRF3 nuclear accumulation assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional reporter and cytokine assays, single lab","pmids":["28768861"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of ternary KIX:c-Myb:HBZ complex shows HBZ activation domain (AD) folds into a long α-helix upon KIX binding, with two tandem amphipathic (L/V)(V/L)DGLL motifs binding the MLL site cooperatively; ITC demonstrates strong cooperativity between c-Myb AD and HBZ for KIX; HBZ bridges two KIX:c-Myb entities simultaneously.","method":"X-ray crystallography, isothermal titration calorimetry (ITC)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus quantitative thermodynamic measurements, multiple orthogonal methods in one study","pmids":["30232260"],"is_preprint":false},{"year":2018,"finding":"UBR5 (an E3 ubiquitin-protein ligase) is a novel HBZ-binding partner; UBR5 ubiquitinates HBZ at seven lysine residues; shRNA knockdown of UBR5 stabilizes HBZ protein by reducing its ubiquitination; UBR5 knockdown decreases T-cell proliferation in transformed lines.","method":"Affinity-tagged protein pulldown with shotgun proteomics, co-immunoprecipitation (overexpression and endogenous), shRNA knockdown, MS/MS identification of ubiquitination sites, proliferation assays","journal":"Frontiers in microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-based discovery confirmed by endogenous Co-IP, ubiquitination site mapping, and functional knockdown assay; multiple orthogonal methods","pmids":["29441057"],"is_preprint":false},{"year":2019,"finding":"HBZ physically interacts with BRG1 (ATPase subunit of SWI/SNF), BAF200, and BAF180 (PBAF signature subunits); BRG1 expression translocates HBZ into distinct nuclear foci; HBZ represses HTLV-1 LTR activation by Tax/BRG1 by deregulating SWI/SNF complex recruitment to the viral promoter (shown by ChIP-qPCR); HBZ also reverses Tax-mediated stabilization of BRG1.","method":"GST pulldown, co-immunoprecipitation, fluorescence microscopy, ChIP-qPCR, luciferase reporter assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pulldown plus Co-IP plus ChIP-qPCR with functional assays, single lab","pmids":["31142665"],"is_preprint":false},{"year":2019,"finding":"HBZ interacts with NF90/NF110 (NFAR proteins) via specific protein domains; HBZ abolishes NF90/110-mediated enhancement of Tax LTR activation; HBZ modulates survivin promoter activity and antagonizes NF110-mediated survivin activation.","method":"GST pulldown, co-immunoprecipitation, luciferase reporter assays","journal":"Virology","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — GST pulldown and Co-IP with reporter assays, single lab, partial mechanistic follow-up","pmids":["27110706"],"is_preprint":false},{"year":2019,"finding":"HBZ is exclusively cytoplasmic in asymptomatic carriers (AC) as well as HAM/TSP patients; the cytoplasmic localization in AC and HAM/TSP is not dependent on THEMIS expression; cells from an HTLV-1-immortalized HAM/TSP cell line confirm HBZ as a cytoplasmic resident protein that does not shuttle to the nucleus.","method":"Immunofluorescence with monoclonal antibody 4D4-F3, confocal microscopy on primary PBMCs and cell lines","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — direct localization with validated antibody on primary patient and carrier cells, replicated across multiple patient groups","pmids":["31080441"],"is_preprint":false},{"year":2020,"finding":"HBZ RNA (independent of protein) interferes with the basal transcription machinery to epigenetically silence HTLV-1 sense (5' LTR) transcription, enabling proviral latency.","method":"RNA expression/functional assays distinguishing RNA vs. protein contributions, transcriptional silencing assays","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic experiments separating RNA vs. protein function, single lab","pmids":["33170933"],"is_preprint":false},{"year":2020,"finding":"HBZ-US (but not HBZ-SI) interacts with HAX-1 in the cytoplasm; HBZ suppresses polyubiquitination of HAX-1 by inhibiting its association with FBXO25 (an SCF E3 ubiquitin ligase component), thereby stabilizing HAX-1 protein; enhanced HAX-1 correlates with suppression of caspase-9 processing, suggesting anti-apoptotic function.","method":"Co-immunoprecipitation, ubiquitination assays, Western blotting with proteasome inhibitor treatment","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assays with functional apoptosis readout, single lab","pmids":["32893878"],"is_preprint":false},{"year":2021,"finding":"HBZ localizes in both cytoplasm and nucleus of ATL patient cells (dual localization), in contrast to exclusive cytoplasmic localization in asymptomatic carriers and HAM/TSP; nuclear translocation of HBZ is associated with neoplastic transformation in ATL.","method":"Immunofluorescence with monoclonal antibody 4D4-F3, confocal microscopy on primary ATL patient cells","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — direct localization with validated antibody on primary ATL patient cells, replicates and extends prior localization studies","pmids":["33626865"],"is_preprint":false},{"year":2021,"finding":"HBZ interacts with U2AF2 (a key pre-mRNA splicing regulator) as part of its interactome; HBZ perturbs the cellular splicing landscape by inducing exon exclusion (opposite to Tax which induces exon inclusion), altering cassette exons in genes also changed in ATLL patient samples.","method":"Interactome mapping (affinity purification-MS), RNA-seq splicing analysis, patient cohort validation","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS interactome plus transcriptomic validation in patient cohorts, single study","pmids":["34543356"],"is_preprint":false},{"year":2021,"finding":"In a Drosophila transgenic model, HBZ does not induce transformation, NF-κB activation, or enhanced PRC2 activity on its own; overexpression of HBZ in tax transgenic flies prevents Tax-induced NF-κB activation, PRC2 activation, transformation, and senescence; both Tax and HBZ directly interact with PRC2 complex core components.","method":"Drosophila transgenic models (hbz-Tg and tax-Tg flies), NF-κB reporter assays, H3K27me3 ChIP, co-immunoprecipitation with PRC2 components","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Drosophila genetic epistasis plus biochemical Co-IP, single lab","pmids":["33471856"],"is_preprint":false},{"year":2023,"finding":"HBZ activates myoferlin (MyoF) expression by forming a complex with c-Jun or JunB at two enhancer sites within the MYOF gene and recruiting p300/CBP coactivator (shown by ChIP); MyoF restricts HTLV-1 envelope (Env) SU trafficking to lysosomes for degradation, thereby maintaining SU levels; MyoF knockdown or inhibition reduces HTLV-1 infection efficiency, cell adhesion, and SU in virus particles.","method":"ChIP assays, qRT-PCR, shRNA knockdown, pharmacological inhibition (WJ460), lysosomal protease inhibitors, LAMP-2 co-localization","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP showing direct promoter occupancy plus multiple orthogonal functional assays (shRNA, drug inhibition, lysosomal rescue), single lab with rigorous controls","pmids":["36827461"],"is_preprint":false},{"year":2023,"finding":"HBZ protein (not hbz mRNA or its stem-loop structure) is critical for HTLV-1 persistence in vivo and leukemogenesis; proviral mutants lacking HBZ protein showed significantly lower proviral loads in rabbits and increased survival of humanized mice, while mRNA stem-loop mutations had no effect.","method":"Proviral mutant viruses, rabbit infection model, humanized immune system (HIS) mouse infection model","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic dissection of HBZ protein vs. mRNA contributions across two animal models","pmids":["37327244"],"is_preprint":false},{"year":2025,"finding":"TGF-β stimulation triggers cytoplasm-to-nucleus translocation of HBZ in ATL cells but not in HTLV-1 carriers; nuclear translocation is mediated by JunB and pSmad3 interacting with HBZ; JUNB knockdown inhibits ATL cell proliferation in vitro and in vivo and promotes apoptosis in ATL but not in non-leukemic HTLV-1-infected cells.","method":"Proximity Ligation Assay on primary cells, co-immunoprecipitation, shRNA knockdown, TGF-β treatment, in vivo xenograft experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PLA-based localization on primary ATL cells plus Co-IP and in vivo knockdown, single lab","pmids":["40549917"],"is_preprint":false},{"year":2025,"finding":"Tax inhibits HBZ RNA splicing by competitively binding splicing factors WDR83 and GPATCH1 (components of the spliceosome), thereby constraining HBZ expression during HTLV-1 early/productive infection; in Tax-negative cells, HBZ is predominantly spliced and active, driving mitotic propagation.","method":"RNA-seq splicing analysis, co-immunoprecipitation of Tax with splicing factors, competitive binding assays","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying Tax-spliceosome interaction plus splicing analysis in Tax+ vs. Tax- cells, single lab","pmids":["40720552"],"is_preprint":false},{"year":2019,"finding":"HBZ regulates RANKL expression in a c-Fos-dependent manner; HBZ transgenic mice develop osteolytic bone lesions and hypercalcemia; RANKL, PTHrP, and DKK1 are upregulated in HBZ-expressing T cells; denosumab (anti-RANKL antibody) alleviates HBZ-driven bone loss in HTLV-1-infected humanized mice.","method":"HBZ-transgenic mice, humanized mouse HTLV-1 infection model, gene expression arrays, pharmacological antibody treatment, patient-derived xenografts","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic/humanized mouse models with pharmacological rescue and molecular pathway analysis, single lab","pmids":["31578308"],"is_preprint":false},{"year":2013,"finding":"HBZ suppresses cyclin D1 transcription via its bZIP domain by binding CREB and inhibiting cyclin D1 promoter activity through the CRE site; confirmed by immunoprecipitation and GST pulldown showing HBZ-bZIP–CREB interaction.","method":"Luciferase reporter assay, RT-PCR, Western blotting, co-immunoprecipitation, GST pulldown","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/GST-pulldown with reporter assay, single lab","pmids":["24065533"],"is_preprint":false},{"year":2010,"finding":"hbz mRNA (not HBZ protein) indirectly promotes Tax expression by down-regulating p30(II) mRNA levels; proviral splice-acceptor mutants that eliminate hbz mRNA reduce tax mRNA, and this is restored by heterologous hbz expression; protein-disrupting mutants alone do not affect tax mRNA levels.","method":"Proviral splice-acceptor and protein-coding mutants, RT-PCR for tax and p30(II) mRNA, heterologous hbz expression rescue","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic dissection of RNA vs. protein function with multiple mutant viruses, single lab","pmids":["21176937"],"is_preprint":false}],"current_model":"HTLV-1 HBZ is a nuclear bZIP protein (also found in the cytoplasm in non-leukemic infected cells) that suppresses viral sense-strand transcription through at least two mechanisms — dimerizing with CREB/ATF factors to block their DNA binding, and binding the KIX domain of p300/CBP (via LXXLL-like/VLDGLL motifs) to competitively displace Tax and inhibit p300/CBP HAT activity; in the cytoplasm it activates mTOR signaling by interacting with GADD34; it modulates AP-1 activity by selectively inhibiting c-Jun (via ubiquitin-independent proteasomal degradation and sequestration into HBZ nuclear bodies) while activating JunD and cooperating with JunB; it represses p53 by inhibiting HAT activity of both p300/CBP and HBO1; it maintains viral latency by inhibiting Rex-dependent export of structural mRNAs; its stability is regulated by UBR5-mediated ubiquitination; TGF-β-triggered JunB/pSmad3 interaction drives its cytoplasm-to-nucleus translocation in ATL cells, and the HBZ protein (not its mRNA) is the critical determinant of viral persistence and leukemogenesis in vivo."},"narrative":{"mechanistic_narrative":"HTLV-1 HBZ is a viral bZIP factor that drives proviral latency and leukemogenesis by reprogramming host transcription, signaling, and protein turnover, and it is the HBZ protein — not its mRNA stem-loop — that is the critical determinant of viral persistence and leukemogenesis in vivo [PMID:12937177, PMID:37327244]. HBZ heterodimerizes through its bZIP domain with the Jun/ATF/Maf families to selectively rewire AP-1 output: it suppresses c-Jun by both blocking its DNA binding and tethering it to the 26S proteasome for ubiquitin-independent degradation, sequesters JunB into HBZ nuclear bodies, yet cooperates with JunD (and Sp1) to activate targets such as the hTERT promoter [PMID:12937177, PMID:17306025, PMID:18078517, PMID:18805793, PMID:19595408]. In parallel, HBZ targets the p300/CBP coactivator: its N-terminal activation domain folds into an α-helix bearing tandem (L/V)(V/L)DGLL motifs that engage the MLL-binding surface of the KIX domain, competitively displacing Tax, while its bZIP domain directly inhibits p300/CBP histone acetyltransferase activity, reducing H3K18 acetylation and repressing viral sense-strand transcription [PMID:18599479, PMID:22434882, PMID:30232260]. Through this coactivator inhibition together with binding and inhibition of HBO1, HBZ represses p53-dependent activation of p21/CDKN1A and GADD45A [PMID:26625199]. HBZ stability is controlled by UBR5-mediated ubiquitination at multiple lysines [PMID:29441057]. HBZ shuttles between compartments via a CRM1-dependent NES; in the cytoplasm it binds GADD34 to activate mTOR signaling and suppress autophagy, and its subcellular distribution tracks disease state — exclusively cytoplasmic in asymptomatic carriers and HAM/TSP but nuclear/dual in ATL, with TGF-β/JunB/pSmad3 driving its cytoplasm-to-nucleus translocation in ATL cells [PMID:23708656, PMID:28095504, PMID:31080441, PMID:33626865, PMID:40549917]. HBZ also enforces latency by inhibiting Rex-dependent export of intron-containing structural mRNAs [PMID:24699669] and promotes infection and oncogenic phenotypes through transcriptional programs including myoferlin induction, CCR4/GATA3-driven T-cell migration, and RANKL-dependent bone lesions [PMID:27402079, PMID:36827461, PMID:31578308].","teleology":[{"year":2003,"claim":"Establishing that HBZ is a bZIP protein that physically heterodimerizes with Jun-family factors defined its core molecular activity as a host transcription modulator rather than a conventional viral transactivator.","evidence":"Reciprocal Co-IP, colocalization, and luciferase/DNA-binding assays in CEM cells","pmids":["12937177"],"confidence":"High","gaps":["Selectivity for c-Jun vs JunB vs JunD not yet mechanistically resolved","No structural basis for differential dimer outcomes"]},{"year":2004,"claim":"Identifying JunD as an activating partner showed HBZ's bZIP engagement produces opposite transcriptional outcomes depending on the partner, and mapped the N-terminus as the activation determinant.","evidence":"In vitro binding, Co-IP, and luciferase reporter assays","pmids":["15044019"],"confidence":"Medium","gaps":["Single lab","Mechanism distinguishing activation from repression unresolved at this stage"]},{"year":2005,"claim":"Discovery that HBZ both blocks c-Jun DNA binding and promotes its proteasomal degradation revealed a dual repression strategy, and subnuclear mapping placed HBZ in nuclear speckles/heterochromatin via multiple NLS.","evidence":"Deletion-mutant reporter and Western assays with proteasome inhibitors; fluorescence and immunogold EM localization","pmids":["15592508","15755797"],"confidence":"Medium","gaps":["Degradation pathway (ubiquitin dependence) not yet defined","Functional consequence of heterochromatin localization unclear"]},{"year":2006,"claim":"Chimera and mutagenesis studies pinpointed the DNA-binding region and a charged-residue cluster controlling Jun transcriptional potency, refining how HBZ tunes AP-1 output, and a spliced isoform was shown to occupy distinct subnuclear sites.","evidence":"HBZ/c-Fos chimeras, mutagenesis with reporters; RACE and immunofluorescence of isoforms","pmids":["16717281","16474156"],"confidence":"Medium","gaps":["Functional difference between spliced and unspliced isoforms not yet established"]},{"year":2007,"claim":"Demonstrating sequestration of JunB into HBZ nuclear bodies and HBZ/JunD cooperation at the hTERT promoter clarified the structural and DNA-occupancy basis of partner-specific outcomes.","evidence":"FRAP and co-transfection reporters; ChIP at the proximal hTERT promoter","pmids":["17306025","18078517"],"confidence":"Medium","gaps":["Single lab","Composition of HBZ nuclear bodies not fully defined"]},{"year":2008,"claim":"Mapping HBZ's LXXLL-like motifs to the KIX domain of p300/CBP and reconstituting an HBZ–c-Jun–26S proteasome complex established two mechanistically distinct repressive activities: coactivator hijacking and ubiquitin-independent substrate delivery.","evidence":"In vitro binding/pulldown with motif mutagenesis and reporters; Co-IP with 26S proteasome plus ubiquitination assays","pmids":["18599479","18805793"],"confidence":"High","gaps":["Whether KIX binding and HAT inhibition are separable not yet tested","Proteasome tethering mechanism not structurally resolved"]},{"year":2010,"claim":"Extending HBZ's bZIP partner repertoire to Maf, ATF2, CEBPG, and CREBZF, with biophysical confirmation, broadened the host network HBZ rewires beyond Jun proteins.","evidence":"Yeast two-hybrid, Co-IP, coiled-coil peptide arrays, circular dichroism, and DNA-binding assays","pmids":["20506502","20102225"],"confidence":"Medium","gaps":["In vivo relevance of MafB/MafG, ATF2, CREBZF interactions not established"]},{"year":2011,"claim":"Refined KIX-surface mapping showed HBZ simultaneously blocks MLL-dependent transcription while allosterically enhancing c-Myb/CREB, and HBZ was shown to blunt Tax-induced senescence via NF-κB downregulation.","evidence":"In vitro binding with domain mutagenesis and reporters; shRNA knockdown with NF-κB and senescence assays","pmids":["21497608","21552325"],"confidence":"Medium","gaps":["Allosteric model not structurally proven at this stage"]},{"year":2012,"claim":"Demonstrating that HBZ directly inhibits p300/CBP HAT activity, lowering H3K18ac in infected cells, established an enzymatic (not just competitive) mechanism of transcriptional repression.","evidence":"In vitro HAT assay with domain mutagenesis and H3K18ac Western in infected vs uninfected cells","pmids":["22434882"],"confidence":"High","gaps":["Genome-wide acetylation consequences not mapped","Single lab"]},{"year":2013,"claim":"Identifying a CRM1-dependent NES and cytoplasmic GADD34 binding revealed HBZ as a spatially regulated signaling effector that activates mTOR and suppresses autophagy outside the nucleus.","evidence":"Leptomycin B treatment, Co-IP domain mapping, S6K phosphorylation and autophagy assays","pmids":["23708656"],"confidence":"Medium","gaps":["Signals controlling nuclear vs cytoplasmic partitioning not yet defined","CREB-mediated cyclin D1 repression (idx 41) rests on a single low-confidence study"]},{"year":2014,"claim":"Showing HBZ inhibits Rex-mediated export of unspliced viral mRNAs and induces BDNF/TrkB survival signaling connected HBZ to both latency maintenance and infected-cell survival.","evidence":"shRNA knockdown, Rex overexpression, viral mRNA export and RT-PCR; ectopic expression with TrkB inhibitor and apoptosis assays","pmids":["24699669","25210182"],"confidence":"Medium","gaps":["Direct HBZ–Rex contact not demonstrated","Single lab for each"]},{"year":2015,"claim":"Endogenous-protein imaging and quantification validated speckle localization and physiological interactions with p300, JunD, CBP, and CREB2 at native expression levels far below overexpression systems.","evidence":"Monoclonal-antibody immunofluorescence, endogenous Co-IP, single-molecule quantification","pmids":["26140924"],"confidence":"Medium","gaps":["Stoichiometry of native complexes not resolved"]},{"year":2016,"claim":"Linking HBZ to p53 repression via inhibition of both p300/CBP and HBO1 HAT activity, plus GATA3/CCR4-driven T-cell migration, connected HBZ's coactivator targeting to tumor-suppressor inactivation and an ATL homing phenotype.","evidence":"Co-IP, in vitro HAT assays, cell-cycle analysis in HCT116; promoter reporters and HBZ-transgenic mouse migration model","pmids":["26625199","27402079"],"confidence":"High","gaps":["Relative contribution of p300/CBP vs HBO1 inhibition to p53 silencing not dissected"]},{"year":2017,"claim":"Patient-cell imaging defined disease-stage-specific localization (cytoplasmic in HAM/TSP), a ΔJunD translation-switch mechanism via RPS25 mRNA retention, and selective modulation of IRF7/IRF3 interferon responses.","evidence":"Validated monoclonal-antibody confocal imaging of PBMCs; ribosomal-protein/JunD isoform biochemistry; Co-IP and IFN reporter/ELISA assays","pmids":["28095504","28260789","28768861"],"confidence":"Medium","gaps":["Determinants forcing exclusive cytoplasmic retention not identified","Single lab for each mechanism"]},{"year":2018,"claim":"The crystal structure of the KIX:c-Myb:HBZ ternary complex provided atomic-level proof that the HBZ AD folds into a helix with cooperative tandem (L/V)(V/L)DGLL motifs, and UBR5 was identified as the E3 ligase controlling HBZ stability.","evidence":"X-ray crystallography and ITC; affinity-MS, endogenous Co-IP, ubiquitination-site mapping, shRNA knockdown","pmids":["30232260","29441057"],"confidence":"High","gaps":["Whether UBR5 turnover is regulated by upstream signals not addressed"]},{"year":2019,"claim":"Discovery of HBZ interactions with SWI/SNF (BRG1/PBAF) and PRC2, and RANKL-driven bone pathology, extended HBZ's reach into chromatin-remodeling control of the viral promoter and to in vivo osteolytic disease.","evidence":"GST pulldown, Co-IP, ChIP-qPCR; Drosophila genetic epistasis with PRC2 Co-IP; HBZ-transgenic/humanized mice with denosumab rescue","pmids":["31142665","33471856","31578308"],"confidence":"Medium","gaps":["NF90/NF110 antagonism (idx 29) is low-confidence and unconfirmed","Direct vs indirect PRC2 effects not fully separated"]},{"year":2020,"claim":"Separating RNA from protein functions showed HBZ RNA epigenetically silences 5' LTR sense transcription, while cytoplasmic HBZ protein stabilizes anti-apoptotic HAX-1 by blocking FBXO25-mediated ubiquitination.","evidence":"RNA-vs-protein functional/silencing assays; Co-IP, ubiquitination assays, caspase-9 readouts","pmids":["33170933","32893878"],"confidence":"Medium","gaps":["Molecular basis of RNA-mediated silencing not resolved","Single lab"]},{"year":2021,"claim":"Mapping the HBZ interactome to splicing machinery (U2AF2) and documenting dual ATL localization tied HBZ to genome-wide exon exclusion and to the nuclear translocation associated with transformation.","evidence":"AP-MS interactome, RNA-seq splicing analysis with patient validation; validated-antibody confocal imaging of ATL cells","pmids":["34543356","33626865"],"confidence":"Medium","gaps":["Trigger for nuclear translocation in ATL not yet identified at this stage"]},{"year":2023,"claim":"Genetic dissection in two animal models proved HBZ protein (not mRNA stem-loop) drives persistence and leukemogenesis, and HBZ was shown to transcriptionally induce myoferlin to protect viral Env from lysosomal degradation.","evidence":"Proviral mutants in rabbit and humanized-mouse infection models; ChIP, shRNA, pharmacological and lysosomal-rescue assays","pmids":["37327244","36827461"],"confidence":"High","gaps":["In vivo contribution of individual HBZ molecular activities not yet partitioned"]},{"year":2025,"claim":"Defining TGF-β/JunB/pSmad3-driven nuclear import in ATL and Tax-mediated splicing control of HBZ expression explained how HBZ activity is switched on during transformation and constrained during early infection.","evidence":"Proximity ligation assay on primary cells, Co-IP, shRNA, xenografts; RNA-seq and competitive splicing-factor binding assays","pmids":["40549917","40720552"],"confidence":"Medium","gaps":["Why TGF-β-triggered import occurs only in ATL and not carriers not mechanistically resolved","Single lab for each"]},{"year":null,"claim":"It remains unresolved how HBZ's many parallel activities — coactivator inhibition, bZIP rewiring, RNA silencing, and cytoplasmic signaling — are coordinated and individually weighted to drive persistence versus transformation in vivo.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking subcellular localization switching to specific oncogenic outputs","Individual molecular activities not yet mutationally separated in animal models","Structural basis of bZIP partner selectivity (c-Jun vs JunB vs JunD) incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,7,8,16,21,36]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,4,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9,16,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,8,16,18]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[31]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[3,5,20,33]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[17,24,30,32,33]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,20,33,38]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,8,16,21,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[37,22,40]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9,27,32]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,19,38]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,25]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[16,28,35]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[18,34,39]}],"complexes":[],"partners":["JUN","JUNB","JUND","CREBBP","EP300","GADD34","UBR5","SMARCA4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P02008","full_name":"Hemoglobin subunit zeta","aliases":["HBAZ","Hemoglobin zeta chain","Zeta-globin"],"length_aa":142,"mass_kda":15.6,"function":"The zeta chain is an alpha-type chain of mammalian embryonic hemoglobin","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P02008/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HBZ","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/HBZ","total_profiled":1310},"omim":[{"mim_id":"614206","title":"CHROMATIN TARGET OF PRMT1; CHTOP","url":"https://www.omim.org/entry/614206"},{"mim_id":"156565","title":"N-@METHYLPURINE DNA GLYCOSYLASE; MPG","url":"https://www.omim.org/entry/156565"},{"mim_id":"142310","title":"HEMOGLOBIN--ZETA LOCUS; HBZ","url":"https://www.omim.org/entry/142310"},{"mim_id":"141800","title":"HEMOGLOBIN--ALPHA LOCUS 1; HBA1","url":"https://www.omim.org/entry/141800"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":3.7},{"tissue":"testis","ntpm":13.9}],"url":"https://www.proteinatlas.org/search/HBZ"},"hgnc":{"alias_symbol":["HBZ1","HBZ-T1"],"prev_symbol":[]},"alphafold":{"accession":"P02008","domains":[{"cath_id":"1.10.490.10","chopping":"6-142","consensus_level":"high","plddt":98.1255,"start":6,"end":142}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P02008","model_url":"https://alphafold.ebi.ac.uk/files/AF-P02008-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P02008-F1-predicted_aligned_error_v6.png","plddt_mean":97.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HBZ","jax_strain_url":"https://www.jax.org/strain/search?query=HBZ"},"sequence":{"accession":"P02008","fasta_url":"https://rest.uniprot.org/uniprotkb/P02008.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P02008/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P02008"}},"corpus_meta":[{"pmid":"21119600","id":"PMC_21119600","title":"Human 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and c-Jun via bZIP domains, suppresses c-Jun-mediated AP-1 transcription by decreasing its DNA-binding activity, enhances JunB transcriptional activity, and inhibits c-Jun-mediated basal expression of the HTLV-1 promoter.\",\n      \"method\": \"Co-immunoprecipitation, cellular colocalization, reporter gene (luciferase) assays, DNA-binding assays in CEM cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus functional reporter assays, independently replicated in multiple subsequent studies\",\n      \"pmids\": [\"12937177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HBZ interacts with JunD in vitro and in vivo via the bZIP domains of both proteins, and stimulates JunD-dependent transcription; the amino-terminus of HBZ is required for transcriptional activation.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation, luciferase reporter assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vitro binding and functional assay, single lab\",\n      \"pmids\": [\"15044019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HBZ suppresses AP-1 activity through a dual mechanism: (1) inhibiting c-Jun DNA-binding activity and (2) promoting proteasome-dependent degradation of c-Jun; both the N-terminal and leucine-zipper regions of HBZ are required for c-Jun elimination.\",\n      \"method\": \"Luciferase assays, Western blotting with proteasome inhibitor treatment, HBZ deletion mutant analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with deletion mutants and pharmacological inhibition, single lab\",\n      \"pmids\": [\"15592508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HBZ nuclear targeting is mediated by three distinct nuclear localization signals (NLS); at least two NLS are necessary for nuclear translocation; wild-type HBZ accumulates in nuclear speckles (not Cajal bodies, splicing factor compartments, or PML bodies); the integrity of the full protein is required for speckle localization; immunogold EM localizes HBZ to heterochromatin.\",\n      \"method\": \"Deletion mutant analysis in mammalian cells, fluorescence microscopy, immunogold electron microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with deletion mutants and EM, single lab\",\n      \"pmids\": [\"15755797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The DNA-binding domain of HBZ is responsible for its inhibitory effect on c-Jun trans-activation; a cluster of six charged amino acids adjacent to the DNA-contact region (a modified Fos-associated cluster) is critical for regulating Jun transcriptional potency, including HBZ's ability to stimulate JunD activity.\",\n      \"method\": \"HBZ/c-Fos chimera construction, reporter gene assays, mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with functional reporter readout, single lab\",\n      \"pmids\": [\"16717281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A spliced isoform of HBZ (HBZ-SI/HBZ-SP1) localizes to distinct subnuclear structures (intense nuclear spots/HBZ-NBs and nucleoli) distinct from the unspliced HBZ isoform, indicating isoform-specific subnuclear targeting.\",\n      \"method\": \"RT-PCR, 5'/3' RACE, Western blotting, immunofluorescence microscopy\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by fluorescence microscopy with isoform-specific constructs, single lab\",\n      \"pmids\": [\"16474156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HBZ-SP1 represses JunB transcriptional activity by sequestering JunB into HBZ nuclear bodies (HBZ-NBs); the ZIP domain of HBZ-SP1 is required for association with HBZ-NBs; JunB co-expression redistributes into HBZ-NBs whereas JunD co-expression results in diffuse nucleoplasmic distribution without NB formation.\",\n      \"method\": \"Fluorescence microscopy, FRAP, co-transfection/reporter assays in COS and HeLa cells\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP plus functional co-transfection assays, single lab\",\n      \"pmids\": [\"17306025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HBZ cooperates with JunD to activate hTERT promoter transcription; HBZ/JunD heterodimers interact with Sp1 and activate hTERT transcription through GC-rich Sp1 binding sites in the proximal hTERT promoter; ChIP confirms HBZ and JunD co-occupy the proximal hTERT promoter region.\",\n      \"method\": \"Co-transfection luciferase assays, RT-PCR for hTERT transcripts, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional reporter assays, single lab\",\n      \"pmids\": [\"18078517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HBZ binds directly to the KIX domain of p300/CBP via two LXXLL-like motifs in its N-terminal activation domain; this interaction specifically targets the MLL-binding surface of KIX, competing with Tax for p300/CBP binding and inhibiting coactivator recruitment to the viral promoter — a second mechanism of HTLV-1 transcriptional repression distinct from CREB dimerization.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding/pulldown assays, luciferase reporter assays, mutagenesis of LXXLL-like motifs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding with mutagenesis plus functional reporter assays, replicated in subsequent structural study\",\n      \"pmids\": [\"18599479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HBZ promotes ubiquitin-independent proteasomal degradation of c-Jun: HBZ directly interacts with both the 26S proteasome and c-Jun, acting as a tethering factor that delivers c-Jun to the proteasome without requiring polyubiquitination.\",\n      \"method\": \"Co-immunoprecipitation with the 26S proteasome, ubiquitination assays, proteasome inhibitor treatment, in vitro binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biochemical reconstitution of proteasome-HBZ-c-Jun complex with ubiquitination assays and mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18805793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The spliced HBZ (sHBZ) isoform shows stronger suppression of Tax-mediated transcriptional activation and promotes T-cell proliferation, while unspliced HBZ (usHBZ) does not promote proliferation; sHBZ transcription from a TATA-less promoter is driven by Sp1 sites and is upregulated by Tax via Tax-responsive elements in the 3' LTR.\",\n      \"method\": \"Luciferase promoter assays, Sp1 site mutagenesis, T-cell proliferation assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays comparing isoforms with promoter mutagenesis, single lab\",\n      \"pmids\": [\"18653454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Repression of c-Jun transcriptional activity by HBZ-SP1 is predominantly due to sequestration of c-Jun into HBZ nuclear bodies rather than inhibition of DNA-binding activity; a DNA-binding-improved HBZ-SP1 chimera retains repressive activity through sequestration.\",\n      \"method\": \"Chimeric mutant construction, DNA-binding assays, fluorescence microscopy, reporter gene assays\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with functional readout plus localization, single lab\",\n      \"pmids\": [\"19595408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HBZ interacts with MafB via bZIP domains, abrogates MafB DNA-binding at Maf recognition elements (MARE), and promotes proteasomal degradation of MafB; identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation and luciferase assays.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, luciferase reporter assay, proteasome inhibitor treatment\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid discovery confirmed by Co-IP and functional assays, single lab\",\n      \"pmids\": [\"20506502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HBZ interacts with MAFB and MAFG via its basic region in a coiled-coil array system; HBZ also forms heterodimers with ATF2, CEBPG, and CREBZF; all new interactions confirmed by circular dichroism in solution; HBZ-MAFB/MAFG heterocomplexes can associate with MARE-site DNA.\",\n      \"method\": \"Coiled-coil peptide arrays, circular dichroism spectroscopy, DNA-binding assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with two orthogonal biophysical methods, single lab\",\n      \"pmids\": [\"20102225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HBZ down-regulates NF-κB activity induced by Tax, thereby alleviating Tax-induced cellular senescence driven by p21(CIP1/WAF1) and p27(KIP1); shRNA-mediated knockdown confirmed that HBZ delays or prevents the onset of Tax-induced senescence.\",\n      \"method\": \"shRNA knockdown, NF-κB reporter assays, senescence assays, cell proliferation assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown with defined functional phenotype (senescence), single lab\",\n      \"pmids\": [\"21552325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HBZ binds to the KIX domain of p300/CBP via two φXXφφ motifs targeting the MLL-binding surface; this simultaneously inhibits MLL-mediated transcription and enhances c-Myb and CREB transcriptional activity by allosterically promoting their binding to the opposite KIX surface.\",\n      \"method\": \"In vitro binding assays, luciferase reporter assays, domain mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding domain mapping with functional assays, single lab\",\n      \"pmids\": [\"21497608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HBZ directly inhibits the histone acetyltransferase (HAT) activity of p300/CBP through its bZIP domain, leading to reduced H3K18 acetylation in HBZ-expressing cells and in HTLV-1-infected cells; HBZ also inhibits acetylation of NF-κB p65 and p53.\",\n      \"method\": \"In vitro HAT activity assay, Western blotting for H3K18ac, comparison of HTLV-1-infected vs. uninfected cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with domain mutagenesis plus cellular validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22434882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HBZ is exported from the nucleus to the cytoplasm via a CRM1-dependent nuclear export signal (NES) in its N-terminal region; in the cytoplasm, HBZ interacts with GADD34 (N-terminal region of HBZ binds C-terminal region of GADD34), activates mTOR signaling (increased S6 kinase phosphorylation), and suppresses starvation-induced autophagy.\",\n      \"method\": \"CRM1 inhibitor (leptomycin B) treatment, co-immunoprecipitation, domain mapping, phosphorylation assays, autophagy assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition of nuclear export plus Co-IP domain mapping and functional signaling assays, single lab\",\n      \"pmids\": [\"23708656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HBZ inhibits Rex-mediated nuclear export of intron-containing (unspliced) viral mRNAs; shRNA-mediated knockdown of HBZ or overexpression of Rex reactivates viral structural protein expression, indicating HBZ maintains HTLV-1 latency partly by blocking Rex function.\",\n      \"method\": \"shRNA knockdown of HBZ, Rex overexpression, viral mRNA nuclear export assays, RT-PCR for viral transcripts\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown and overexpression with defined molecular phenotype, single lab\",\n      \"pmids\": [\"24699669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HBZ activates BDNF expression in HTLV-1-infected T cells; elevated BDNF and its receptor TrkB are found in HTLV-1-infected T-cell lines; chemical inhibition of TrkB signaling increases apoptosis in HTLV-1-infected cells and reduces phosphorylation of GSK-3β, demonstrating a functional BDNF/TrkB autocrine/paracrine survival signaling loop promoted by HBZ.\",\n      \"method\": \"Ectopic HBZ expression, RT-PCR/Western blotting for BDNF and TrkB, TrkB chemical inhibitor treatment, apoptosis assays, phosphorylation assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ectopic expression plus pharmacological inhibition with defined functional phenotype, single lab\",\n      \"pmids\": [\"25210182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Endogenous HBZ protein in HTLV-1-infected and ATL cells localizes in speckle-like nuclear structures; endogenous HBZ interacts with p300, JunD, and partially co-localizes with CBP and CREB2 in vivo; quantified at 17,000–40,000 molecules per cell (20–50-fold less than in overexpression systems).\",\n      \"method\": \"Monoclonal antibody immunofluorescence, confocal microscopy, co-immunoprecipitation with endogenous protein, single-molecule quantification\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous protein localization and Co-IP with validated monoclonal antibody, single lab\",\n      \"pmids\": [\"26140924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HBZ represses p53 activity by directly inhibiting the HAT activity of p300/CBP (reducing p53 acetylation) and by binding to and inhibiting the HAT activity of HBO1 (a p53 coactivator at the p21/CDKN1A promoter), leading to impaired p53-dependent activation of p21/CDKN1A and GADD45A and delay in G2 arrest.\",\n      \"method\": \"Co-immunoprecipitation, in vitro HAT activity assay, luciferase/gene expression assays, cell cycle analysis in HCT116 p53+/+ cells\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay, Co-IP, and functional cellular assays with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"26625199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HBZ induces CCR4 expression in CD4+ T cells by activating GATA3, which in turn activates CCR4 promoter transcription; HBZ silencing in ATL cell lines inhibits CCR4 expression; in HBZ-transgenic mice, CD4+ T cells migrate preferentially and proliferate in response to CCR4 ligands CCL17/CCL22 and CD103 ligand E-cadherin.\",\n      \"method\": \"Ectopic HBZ expression, shRNA knockdown, promoter reporter assays, HBZ-transgenic mouse air-pouch migration model, CCR4 antagonist treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mechanistic assays corroborated by transgenic mouse model with pharmacological inhibition, single lab\",\n      \"pmids\": [\"27402079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HBZ induces expression of the ΔJunD isoform (N-terminal truncated, oncogenic) by causing nuclear retention of RPS25 mRNA and loss of RPS25 protein, a small ribosomal subunit component; loss of RPS25 bypasses translational control of the JunD upstream open reading frame (uORF), shifting translation initiation to produce ΔJunD, which promotes cell proliferation and transformation.\",\n      \"method\": \"Western blotting for JunD isoforms, qRT-PCR for RPS25 mRNA, ChIP for JunD promoter, cell proliferation and transformation assays, nuclear fractionation\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus biochemical fractionation and functional proliferation assays, single lab\",\n      \"pmids\": [\"28260789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HBZ localizes exclusively in the cytoplasm of PBMCs from HAM/TSP patients; in ATL cell lines it localizes in the nucleus; HBZ and Tax-1 are rarely co-expressed in the same cell in HAM/TSP patients; cytoplasmic HBZ is found almost exclusively in CD4+ T cells.\",\n      \"method\": \"Immunofluorescence with validated monoclonal antibody 4D4-F3, confocal microscopy, PBMC fractionation and cell-type analysis\",\n      \"journal\": \"PLoS neglected tropical diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with validated antibody on primary patient cells, single lab; replicated in subsequent studies\",\n      \"pmids\": [\"28095504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HBZ enhances IRF7-induced IFN-α and ISRE promoter activity and IFN-α production, and enhances IRF7 activation by TBK1/IKKε; conversely, HBZ cooperates with Tax to suppress IRF3-induced IFN-β; HBZ physically interacts with IRF7 and IKKε but not with IRF3 or TBK1.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assays, IFN-α ELISA, IRF3 nuclear accumulation assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional reporter and cytokine assays, single lab\",\n      \"pmids\": [\"28768861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of ternary KIX:c-Myb:HBZ complex shows HBZ activation domain (AD) folds into a long α-helix upon KIX binding, with two tandem amphipathic (L/V)(V/L)DGLL motifs binding the MLL site cooperatively; ITC demonstrates strong cooperativity between c-Myb AD and HBZ for KIX; HBZ bridges two KIX:c-Myb entities simultaneously.\",\n      \"method\": \"X-ray crystallography, isothermal titration calorimetry (ITC)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus quantitative thermodynamic measurements, multiple orthogonal methods in one study\",\n      \"pmids\": [\"30232260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"UBR5 (an E3 ubiquitin-protein ligase) is a novel HBZ-binding partner; UBR5 ubiquitinates HBZ at seven lysine residues; shRNA knockdown of UBR5 stabilizes HBZ protein by reducing its ubiquitination; UBR5 knockdown decreases T-cell proliferation in transformed lines.\",\n      \"method\": \"Affinity-tagged protein pulldown with shotgun proteomics, co-immunoprecipitation (overexpression and endogenous), shRNA knockdown, MS/MS identification of ubiquitination sites, proliferation assays\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-based discovery confirmed by endogenous Co-IP, ubiquitination site mapping, and functional knockdown assay; multiple orthogonal methods\",\n      \"pmids\": [\"29441057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HBZ physically interacts with BRG1 (ATPase subunit of SWI/SNF), BAF200, and BAF180 (PBAF signature subunits); BRG1 expression translocates HBZ into distinct nuclear foci; HBZ represses HTLV-1 LTR activation by Tax/BRG1 by deregulating SWI/SNF complex recruitment to the viral promoter (shown by ChIP-qPCR); HBZ also reverses Tax-mediated stabilization of BRG1.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, fluorescence microscopy, ChIP-qPCR, luciferase reporter assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pulldown plus Co-IP plus ChIP-qPCR with functional assays, single lab\",\n      \"pmids\": [\"31142665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HBZ interacts with NF90/NF110 (NFAR proteins) via specific protein domains; HBZ abolishes NF90/110-mediated enhancement of Tax LTR activation; HBZ modulates survivin promoter activity and antagonizes NF110-mediated survivin activation.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, luciferase reporter assays\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — GST pulldown and Co-IP with reporter assays, single lab, partial mechanistic follow-up\",\n      \"pmids\": [\"27110706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HBZ is exclusively cytoplasmic in asymptomatic carriers (AC) as well as HAM/TSP patients; the cytoplasmic localization in AC and HAM/TSP is not dependent on THEMIS expression; cells from an HTLV-1-immortalized HAM/TSP cell line confirm HBZ as a cytoplasmic resident protein that does not shuttle to the nucleus.\",\n      \"method\": \"Immunofluorescence with monoclonal antibody 4D4-F3, confocal microscopy on primary PBMCs and cell lines\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization with validated antibody on primary patient and carrier cells, replicated across multiple patient groups\",\n      \"pmids\": [\"31080441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HBZ RNA (independent of protein) interferes with the basal transcription machinery to epigenetically silence HTLV-1 sense (5' LTR) transcription, enabling proviral latency.\",\n      \"method\": \"RNA expression/functional assays distinguishing RNA vs. protein contributions, transcriptional silencing assays\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic experiments separating RNA vs. protein function, single lab\",\n      \"pmids\": [\"33170933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HBZ-US (but not HBZ-SI) interacts with HAX-1 in the cytoplasm; HBZ suppresses polyubiquitination of HAX-1 by inhibiting its association with FBXO25 (an SCF E3 ubiquitin ligase component), thereby stabilizing HAX-1 protein; enhanced HAX-1 correlates with suppression of caspase-9 processing, suggesting anti-apoptotic function.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, Western blotting with proteasome inhibitor treatment\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assays with functional apoptosis readout, single lab\",\n      \"pmids\": [\"32893878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HBZ localizes in both cytoplasm and nucleus of ATL patient cells (dual localization), in contrast to exclusive cytoplasmic localization in asymptomatic carriers and HAM/TSP; nuclear translocation of HBZ is associated with neoplastic transformation in ATL.\",\n      \"method\": \"Immunofluorescence with monoclonal antibody 4D4-F3, confocal microscopy on primary ATL patient cells\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization with validated antibody on primary ATL patient cells, replicates and extends prior localization studies\",\n      \"pmids\": [\"33626865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HBZ interacts with U2AF2 (a key pre-mRNA splicing regulator) as part of its interactome; HBZ perturbs the cellular splicing landscape by inducing exon exclusion (opposite to Tax which induces exon inclusion), altering cassette exons in genes also changed in ATLL patient samples.\",\n      \"method\": \"Interactome mapping (affinity purification-MS), RNA-seq splicing analysis, patient cohort validation\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS interactome plus transcriptomic validation in patient cohorts, single study\",\n      \"pmids\": [\"34543356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In a Drosophila transgenic model, HBZ does not induce transformation, NF-κB activation, or enhanced PRC2 activity on its own; overexpression of HBZ in tax transgenic flies prevents Tax-induced NF-κB activation, PRC2 activation, transformation, and senescence; both Tax and HBZ directly interact with PRC2 complex core components.\",\n      \"method\": \"Drosophila transgenic models (hbz-Tg and tax-Tg flies), NF-κB reporter assays, H3K27me3 ChIP, co-immunoprecipitation with PRC2 components\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Drosophila genetic epistasis plus biochemical Co-IP, single lab\",\n      \"pmids\": [\"33471856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HBZ activates myoferlin (MyoF) expression by forming a complex with c-Jun or JunB at two enhancer sites within the MYOF gene and recruiting p300/CBP coactivator (shown by ChIP); MyoF restricts HTLV-1 envelope (Env) SU trafficking to lysosomes for degradation, thereby maintaining SU levels; MyoF knockdown or inhibition reduces HTLV-1 infection efficiency, cell adhesion, and SU in virus particles.\",\n      \"method\": \"ChIP assays, qRT-PCR, shRNA knockdown, pharmacological inhibition (WJ460), lysosomal protease inhibitors, LAMP-2 co-localization\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP showing direct promoter occupancy plus multiple orthogonal functional assays (shRNA, drug inhibition, lysosomal rescue), single lab with rigorous controls\",\n      \"pmids\": [\"36827461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HBZ protein (not hbz mRNA or its stem-loop structure) is critical for HTLV-1 persistence in vivo and leukemogenesis; proviral mutants lacking HBZ protein showed significantly lower proviral loads in rabbits and increased survival of humanized mice, while mRNA stem-loop mutations had no effect.\",\n      \"method\": \"Proviral mutant viruses, rabbit infection model, humanized immune system (HIS) mouse infection model\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic dissection of HBZ protein vs. mRNA contributions across two animal models\",\n      \"pmids\": [\"37327244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TGF-β stimulation triggers cytoplasm-to-nucleus translocation of HBZ in ATL cells but not in HTLV-1 carriers; nuclear translocation is mediated by JunB and pSmad3 interacting with HBZ; JUNB knockdown inhibits ATL cell proliferation in vitro and in vivo and promotes apoptosis in ATL but not in non-leukemic HTLV-1-infected cells.\",\n      \"method\": \"Proximity Ligation Assay on primary cells, co-immunoprecipitation, shRNA knockdown, TGF-β treatment, in vivo xenograft experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PLA-based localization on primary ATL cells plus Co-IP and in vivo knockdown, single lab\",\n      \"pmids\": [\"40549917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Tax inhibits HBZ RNA splicing by competitively binding splicing factors WDR83 and GPATCH1 (components of the spliceosome), thereby constraining HBZ expression during HTLV-1 early/productive infection; in Tax-negative cells, HBZ is predominantly spliced and active, driving mitotic propagation.\",\n      \"method\": \"RNA-seq splicing analysis, co-immunoprecipitation of Tax with splicing factors, competitive binding assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying Tax-spliceosome interaction plus splicing analysis in Tax+ vs. Tax- cells, single lab\",\n      \"pmids\": [\"40720552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HBZ regulates RANKL expression in a c-Fos-dependent manner; HBZ transgenic mice develop osteolytic bone lesions and hypercalcemia; RANKL, PTHrP, and DKK1 are upregulated in HBZ-expressing T cells; denosumab (anti-RANKL antibody) alleviates HBZ-driven bone loss in HTLV-1-infected humanized mice.\",\n      \"method\": \"HBZ-transgenic mice, humanized mouse HTLV-1 infection model, gene expression arrays, pharmacological antibody treatment, patient-derived xenografts\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic/humanized mouse models with pharmacological rescue and molecular pathway analysis, single lab\",\n      \"pmids\": [\"31578308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HBZ suppresses cyclin D1 transcription via its bZIP domain by binding CREB and inhibiting cyclin D1 promoter activity through the CRE site; confirmed by immunoprecipitation and GST pulldown showing HBZ-bZIP–CREB interaction.\",\n      \"method\": \"Luciferase reporter assay, RT-PCR, Western blotting, co-immunoprecipitation, GST pulldown\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/GST-pulldown with reporter assay, single lab\",\n      \"pmids\": [\"24065533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"hbz mRNA (not HBZ protein) indirectly promotes Tax expression by down-regulating p30(II) mRNA levels; proviral splice-acceptor mutants that eliminate hbz mRNA reduce tax mRNA, and this is restored by heterologous hbz expression; protein-disrupting mutants alone do not affect tax mRNA levels.\",\n      \"method\": \"Proviral splice-acceptor and protein-coding mutants, RT-PCR for tax and p30(II) mRNA, heterologous hbz expression rescue\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic dissection of RNA vs. protein function with multiple mutant viruses, single lab\",\n      \"pmids\": [\"21176937\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HTLV-1 HBZ is a nuclear bZIP protein (also found in the cytoplasm in non-leukemic infected cells) that suppresses viral sense-strand transcription through at least two mechanisms — dimerizing with CREB/ATF factors to block their DNA binding, and binding the KIX domain of p300/CBP (via LXXLL-like/VLDGLL motifs) to competitively displace Tax and inhibit p300/CBP HAT activity; in the cytoplasm it activates mTOR signaling by interacting with GADD34; it modulates AP-1 activity by selectively inhibiting c-Jun (via ubiquitin-independent proteasomal degradation and sequestration into HBZ nuclear bodies) while activating JunD and cooperating with JunB; it represses p53 by inhibiting HAT activity of both p300/CBP and HBO1; it maintains viral latency by inhibiting Rex-dependent export of structural mRNAs; its stability is regulated by UBR5-mediated ubiquitination; TGF-β-triggered JunB/pSmad3 interaction drives its cytoplasm-to-nucleus translocation in ATL cells, and the HBZ protein (not its mRNA) is the critical determinant of viral persistence and leukemogenesis in vivo.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HTLV-1 HBZ is a viral bZIP factor that drives proviral latency and leukemogenesis by reprogramming host transcription, signaling, and protein turnover, and it is the HBZ protein — not its mRNA stem-loop — that is the critical determinant of viral persistence and leukemogenesis in vivo [#0, #37]. HBZ heterodimerizes through its bZIP domain with the Jun/ATF/Maf families to selectively rewire AP-1 output: it suppresses c-Jun by both blocking its DNA binding and tethering it to the 26S proteasome for ubiquitin-independent degradation, sequesters JunB into HBZ nuclear bodies, yet cooperates with JunD (and Sp1) to activate targets such as the hTERT promoter [#0, #6, #7, #9, #11]. In parallel, HBZ targets the p300/CBP coactivator: its N-terminal activation domain folds into an α-helix bearing tandem (L/V)(V/L)DGLL motifs that engage the MLL-binding surface of the KIX domain, competitively displacing Tax, while its bZIP domain directly inhibits p300/CBP histone acetyltransferase activity, reducing H3K18 acetylation and repressing viral sense-strand transcription [#8, #16, #26]. Through this coactivator inhibition together with binding and inhibition of HBO1, HBZ represses p53-dependent activation of p21/CDKN1A and GADD45A [#21]. HBZ stability is controlled by UBR5-mediated ubiquitination at multiple lysines [#27]. HBZ shuttles between compartments via a CRM1-dependent NES; in the cytoplasm it binds GADD34 to activate mTOR signaling and suppress autophagy, and its subcellular distribution tracks disease state — exclusively cytoplasmic in asymptomatic carriers and HAM/TSP but nuclear/dual in ATL, with TGF-β/JunB/pSmad3 driving its cytoplasm-to-nucleus translocation in ATL cells [#17, #24, #30, #33, #38]. HBZ also enforces latency by inhibiting Rex-dependent export of intron-containing structural mRNAs [#18] and promotes infection and oncogenic phenotypes through transcriptional programs including myoferlin induction, CCR4/GATA3-driven T-cell migration, and RANKL-dependent bone lesions [#22, #36, #40].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that HBZ is a bZIP protein that physically heterodimerizes with Jun-family factors defined its core molecular activity as a host transcription modulator rather than a conventional viral transactivator.\",\n      \"evidence\": \"Reciprocal Co-IP, colocalization, and luciferase/DNA-binding assays in CEM cells\",\n      \"pmids\": [\"12937177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity for c-Jun vs JunB vs JunD not yet mechanistically resolved\", \"No structural basis for differential dimer outcomes\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying JunD as an activating partner showed HBZ's bZIP engagement produces opposite transcriptional outcomes depending on the partner, and mapped the N-terminus as the activation determinant.\",\n      \"evidence\": \"In vitro binding, Co-IP, and luciferase reporter assays\",\n      \"pmids\": [\"15044019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism distinguishing activation from repression unresolved at this stage\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that HBZ both blocks c-Jun DNA binding and promotes its proteasomal degradation revealed a dual repression strategy, and subnuclear mapping placed HBZ in nuclear speckles/heterochromatin via multiple NLS.\",\n      \"evidence\": \"Deletion-mutant reporter and Western assays with proteasome inhibitors; fluorescence and immunogold EM localization\",\n      \"pmids\": [\"15592508\", \"15755797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation pathway (ubiquitin dependence) not yet defined\", \"Functional consequence of heterochromatin localization unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Chimera and mutagenesis studies pinpointed the DNA-binding region and a charged-residue cluster controlling Jun transcriptional potency, refining how HBZ tunes AP-1 output, and a spliced isoform was shown to occupy distinct subnuclear sites.\",\n      \"evidence\": \"HBZ/c-Fos chimeras, mutagenesis with reporters; RACE and immunofluorescence of isoforms\",\n      \"pmids\": [\"16717281\", \"16474156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional difference between spliced and unspliced isoforms not yet established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating sequestration of JunB into HBZ nuclear bodies and HBZ/JunD cooperation at the hTERT promoter clarified the structural and DNA-occupancy basis of partner-specific outcomes.\",\n      \"evidence\": \"FRAP and co-transfection reporters; ChIP at the proximal hTERT promoter\",\n      \"pmids\": [\"17306025\", \"18078517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Composition of HBZ nuclear bodies not fully defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapping HBZ's LXXLL-like motifs to the KIX domain of p300/CBP and reconstituting an HBZ–c-Jun–26S proteasome complex established two mechanistically distinct repressive activities: coactivator hijacking and ubiquitin-independent substrate delivery.\",\n      \"evidence\": \"In vitro binding/pulldown with motif mutagenesis and reporters; Co-IP with 26S proteasome plus ubiquitination assays\",\n      \"pmids\": [\"18599479\", \"18805793\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KIX binding and HAT inhibition are separable not yet tested\", \"Proteasome tethering mechanism not structurally resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extending HBZ's bZIP partner repertoire to Maf, ATF2, CEBPG, and CREBZF, with biophysical confirmation, broadened the host network HBZ rewires beyond Jun proteins.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, coiled-coil peptide arrays, circular dichroism, and DNA-binding assays\",\n      \"pmids\": [\"20506502\", \"20102225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of MafB/MafG, ATF2, CREBZF interactions not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Refined KIX-surface mapping showed HBZ simultaneously blocks MLL-dependent transcription while allosterically enhancing c-Myb/CREB, and HBZ was shown to blunt Tax-induced senescence via NF-κB downregulation.\",\n      \"evidence\": \"In vitro binding with domain mutagenesis and reporters; shRNA knockdown with NF-κB and senescence assays\",\n      \"pmids\": [\"21497608\", \"21552325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Allosteric model not structurally proven at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that HBZ directly inhibits p300/CBP HAT activity, lowering H3K18ac in infected cells, established an enzymatic (not just competitive) mechanism of transcriptional repression.\",\n      \"evidence\": \"In vitro HAT assay with domain mutagenesis and H3K18ac Western in infected vs uninfected cells\",\n      \"pmids\": [\"22434882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide acetylation consequences not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying a CRM1-dependent NES and cytoplasmic GADD34 binding revealed HBZ as a spatially regulated signaling effector that activates mTOR and suppresses autophagy outside the nucleus.\",\n      \"evidence\": \"Leptomycin B treatment, Co-IP domain mapping, S6K phosphorylation and autophagy assays\",\n      \"pmids\": [\"23708656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals controlling nuclear vs cytoplasmic partitioning not yet defined\", \"CREB-mediated cyclin D1 repression (idx 41) rests on a single low-confidence study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing HBZ inhibits Rex-mediated export of unspliced viral mRNAs and induces BDNF/TrkB survival signaling connected HBZ to both latency maintenance and infected-cell survival.\",\n      \"evidence\": \"shRNA knockdown, Rex overexpression, viral mRNA export and RT-PCR; ectopic expression with TrkB inhibitor and apoptosis assays\",\n      \"pmids\": [\"24699669\", \"25210182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HBZ–Rex contact not demonstrated\", \"Single lab for each\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Endogenous-protein imaging and quantification validated speckle localization and physiological interactions with p300, JunD, CBP, and CREB2 at native expression levels far below overexpression systems.\",\n      \"evidence\": \"Monoclonal-antibody immunofluorescence, endogenous Co-IP, single-molecule quantification\",\n      \"pmids\": [\"26140924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of native complexes not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linking HBZ to p53 repression via inhibition of both p300/CBP and HBO1 HAT activity, plus GATA3/CCR4-driven T-cell migration, connected HBZ's coactivator targeting to tumor-suppressor inactivation and an ATL homing phenotype.\",\n      \"evidence\": \"Co-IP, in vitro HAT assays, cell-cycle analysis in HCT116; promoter reporters and HBZ-transgenic mouse migration model\",\n      \"pmids\": [\"26625199\", \"27402079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of p300/CBP vs HBO1 inhibition to p53 silencing not dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Patient-cell imaging defined disease-stage-specific localization (cytoplasmic in HAM/TSP), a ΔJunD translation-switch mechanism via RPS25 mRNA retention, and selective modulation of IRF7/IRF3 interferon responses.\",\n      \"evidence\": \"Validated monoclonal-antibody confocal imaging of PBMCs; ribosomal-protein/JunD isoform biochemistry; Co-IP and IFN reporter/ELISA assays\",\n      \"pmids\": [\"28095504\", \"28260789\", \"28768861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants forcing exclusive cytoplasmic retention not identified\", \"Single lab for each mechanism\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The crystal structure of the KIX:c-Myb:HBZ ternary complex provided atomic-level proof that the HBZ AD folds into a helix with cooperative tandem (L/V)(V/L)DGLL motifs, and UBR5 was identified as the E3 ligase controlling HBZ stability.\",\n      \"evidence\": \"X-ray crystallography and ITC; affinity-MS, endogenous Co-IP, ubiquitination-site mapping, shRNA knockdown\",\n      \"pmids\": [\"30232260\", \"29441057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether UBR5 turnover is regulated by upstream signals not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery of HBZ interactions with SWI/SNF (BRG1/PBAF) and PRC2, and RANKL-driven bone pathology, extended HBZ's reach into chromatin-remodeling control of the viral promoter and to in vivo osteolytic disease.\",\n      \"evidence\": \"GST pulldown, Co-IP, ChIP-qPCR; Drosophila genetic epistasis with PRC2 Co-IP; HBZ-transgenic/humanized mice with denosumab rescue\",\n      \"pmids\": [\"31142665\", \"33471856\", \"31578308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NF90/NF110 antagonism (idx 29) is low-confidence and unconfirmed\", \"Direct vs indirect PRC2 effects not fully separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Separating RNA from protein functions showed HBZ RNA epigenetically silences 5' LTR sense transcription, while cytoplasmic HBZ protein stabilizes anti-apoptotic HAX-1 by blocking FBXO25-mediated ubiquitination.\",\n      \"evidence\": \"RNA-vs-protein functional/silencing assays; Co-IP, ubiquitination assays, caspase-9 readouts\",\n      \"pmids\": [\"33170933\", \"32893878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of RNA-mediated silencing not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapping the HBZ interactome to splicing machinery (U2AF2) and documenting dual ATL localization tied HBZ to genome-wide exon exclusion and to the nuclear translocation associated with transformation.\",\n      \"evidence\": \"AP-MS interactome, RNA-seq splicing analysis with patient validation; validated-antibody confocal imaging of ATL cells\",\n      \"pmids\": [\"34543356\", \"33626865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trigger for nuclear translocation in ATL not yet identified at this stage\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Genetic dissection in two animal models proved HBZ protein (not mRNA stem-loop) drives persistence and leukemogenesis, and HBZ was shown to transcriptionally induce myoferlin to protect viral Env from lysosomal degradation.\",\n      \"evidence\": \"Proviral mutants in rabbit and humanized-mouse infection models; ChIP, shRNA, pharmacological and lysosomal-rescue assays\",\n      \"pmids\": [\"37327244\", \"36827461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of individual HBZ molecular activities not yet partitioned\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining TGF-β/JunB/pSmad3-driven nuclear import in ATL and Tax-mediated splicing control of HBZ expression explained how HBZ activity is switched on during transformation and constrained during early infection.\",\n      \"evidence\": \"Proximity ligation assay on primary cells, Co-IP, shRNA, xenografts; RNA-seq and competitive splicing-factor binding assays\",\n      \"pmids\": [\"40549917\", \"40720552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why TGF-β-triggered import occurs only in ATL and not carriers not mechanistically resolved\", \"Single lab for each\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how HBZ's many parallel activities — coactivator inhibition, bZIP rewiring, RNA silencing, and cytoplasmic signaling — are coordinated and individually weighted to drive persistence versus transformation in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking subcellular localization switching to specific oncogenic outputs\", \"Individual molecular activities not yet mutationally separated in animal models\", \"Structural basis of bZIP partner selectivity (c-Jun vs JunB vs JunD) incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 7, 8, 16, 21, 36]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 4, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9, 16, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 8, 16, 18]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [3, 5, 20, 33]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17, 24, 30, 32, 33]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 20, 33, 38]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 8, 16, 21, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [37, 22, 40]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 27, 32]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 19, 38]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 25]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [16, 28, 35]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [18, 34, 39]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"JUN\", \"JUNB\", \"JUND\", \"CREBBP\", \"EP300\", \"GADD34\", \"UBR5\", \"SMARCA4\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}