Affinage

TANGO6

Transport and Golgi organization protein 6 homolog · UniProt Q9C0B7

Round 2 corrected
Length
1094 aa
Mass
120.7 kDa
Annotated
2026-04-28
33 papers in source corpus 2 papers cited in narrative 2 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TANGO6 is a two-transmembrane COPI vesicle-associated protein that functions in retrograde Golgi-to-ER transport to deliver RNA polymerase II subunit B (RPB2) to the nucleus. During G1 phase, TANGO6 captures RPB2 at the cis-Golgi via its cytoplasmic N- and C-terminal domains and directs RPB2 through COPI-mediated retrograde trafficking to the ER and onward to the nucleus; loss of TANGO6 causes cytoplasmic RPB2 accumulation, DNA damage, and G1 cell-cycle arrest (PMID:38490996). TANGO6 is essential for hematopoietic stem/progenitor cell expansion in both mouse and zebrafish, acting through a P53–Ikzf1/Cmyb transcriptional axis downstream of RPB2 depletion (PMID:38490996, PMID:39620979).

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2024 High

    Resolved how TANGO6 participates in intracellular trafficking: it integrates into COPI vesicles via two transmembrane domains and uses cytoplasmic termini to capture RPB2 at the cis-Golgi, establishing a previously unknown Golgi-to-ER-to-nucleus transport route for a core transcriptional machinery subunit.

    Evidence Co-immunoprecipitation, live-cell imaging, transmembrane-domain mutagenesis, cell-cycle analysis, and conditional mouse HSC knockout/overexpression (mammalian cell lines and mouse model)

    PMID:38490996

    Open questions at the time
    • Whether TANGO6 transports cargo other than RPB2 is unknown
    • Structural basis for RPB2 recognition by the TANGO6 cytoplasmic termini has not been determined
    • How RPB2 transitions from the ER lumen/membrane to the nucleoplasm after COPI-mediated retrograde delivery is unresolved
  2. 2025 High

    Genetic epistasis in zebrafish placed TANGO6 upstream of a P53–Ikzf1/Cmyb axis, showing that RPB2 depletion upon tango6 loss triggers DNA damage and P53-dependent suppression of hematopoietic transcription factors, thereby explaining the HSPC expansion defect.

    Evidence Large-scale zebrafish genetic screen, homozygous tango6 mutant phenotyping, haematopoietic rescue by ikzf1/cmyb overexpression, DNA damage assays, and RPB2 Western blot

    PMID:39620979

    Open questions at the time
    • Whether P53 activation is a direct consequence of RPB2 loss or of broader transcriptional stress has not been dissected
    • Relevance of the Tango6–P53–Ikzf1/Cmyb axis in mammalian hematopoiesis beyond the mouse conditional knockout has not been tested
    • Whether TANGO6 loss affects non-hematopoietic stem cell populations in vivo is unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • Open question: how TANGO6 selectively recognizes RPB2 among Golgi-localized proteins, whether additional cargo substrates exist, and what triggers cell-cycle-phase-specific (G1) engagement of the TANGO6–COPI transport route remain unresolved.
  • No structural or biochemical reconstitution of the TANGO6–RPB2 interaction has been reported
  • Mechanism of G1-phase specificity is unknown
  • Potential roles in Golgi organization independent of RPB2 transport have not been addressed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 1
Localization
GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 1 R-HSA-9609507 Protein localization 1
Partners
POLR2B

Evidence

Reading pass · 2 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2024 TANGO6 associates with COPI vesicles via two transmembrane domains and uses its N- and C-terminal cytoplasmic fragments to capture RNA polymerase II subunit B (RPB2) at the cis-Golgi during the G1 phase. COPI-docked TANGO6 then carries RPB2 from the Golgi to the ER and subsequently to the nucleus. Functional disruption of TANGO6 blocks RPB2 nuclear entry, causing cytoplasmic accumulation of RPB2 and G1 phase cell cycle arrest. Conditional depletion or overexpression of TANGO6 in mouse hematopoietic stem cells results in compromised or expanded hematopoiesis, respectively. Co-immunoprecipitation, live-cell imaging, domain mutagenesis (transmembrane domain disruption), cell cycle analysis (flow cytometry), conditional mouse knockout/overexpression of TANGO6 in HSCs Nature Communications High 38490996
2025 In zebrafish, tango6 is indispensable for HSPC proliferation and definitive haematopoiesis in the caudal haematopoietic tissue. Homozygous tango6 mutants show defective HSPC expansion; tango6 deficiency causes decline in RNA polymerase II subunit B and accumulation of DNA damage, suppressing cell expansion in a P53-dependent manner. The haematopoietic transcription factors Ikzf1 and Cmyb are downstream P53 targets used by tango6 in haematopoiesis, and partial recovery of the haematopoietic phenotype is achieved by compensating for loss of ikzf1 and cmyb in tango6 mutants, defining a Tango6–P53–Ikzf1/Cmyb axis. Large-scale genetic screen in zebrafish, homozygous mutant analysis, haematopoietic overexpression rescue experiments, epistasis (tango6 mutant + ikzf1/cmyb rescue), DNA damage assays, Western blot for RPB2 Development (Cambridge, England) High 39620979

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2022 Human transcription factor protein interaction networks. Nature communications 123 35140242
2022 Identification and functional characterization of transcriptional activators in human cells. Molecular cell 98 35016035
2017 R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 to regulate assembly of U5 small nuclear ribonucleoprotein. Nature communications 94 28561026
2002 Protein-protein interactions between large proteins: two-hybrid screening using a functionally classified library composed of long cDNAs. Genome research 82 12421765
2000 Prediction of the coding sequences of unidentified human genes. XIX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA research : an international journal for rapid publication of reports on genes and genomes 81 11214970
2016 Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways. Cell reports 77 26972000
2017 A Role for Mitochondrial Translation in Promotion of Viability in K-Ras Mutant Cells. Cell reports 64 28700943
2018 Network Analysis of UBE3A/E6AP-Associated Proteins Provides Connections to Several Distinct Cellular Processes. Journal of molecular biology 41 29426014
2015 Protein interactome mining defines melatonin MT1 receptors as integral component of presynaptic protein complexes of neurons. Journal of pineal research 39 26514267
2021 Integrative oncogene-dependency mapping identifies RIT1 vulnerabilities and synergies in lung cancer. Nature communications 36 34373451
2019 Whole-genome analysis identifying candidate genes of altitude adaptive ecological thresholds in yak populations. Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie 24 31062447
2019 BioID Performed on Golgi Enriched Fractions Identify C10orf76 as a GBF1 Binding Protein Essential for Golgi Maintenance and Secretion. Molecular & cellular proteomics : MCP 23 31519766
2022 ESCPE-1 mediates retrograde endosomal sorting of the SARS-CoV-2 host factor Neuropilin-1. Proceedings of the National Academy of Sciences of the United States of America 22 35696571
2022 HSF1 phosphorylation establishes an active chromatin state via the TRRAP-TIP60 complex and promotes tumorigenesis. Nature communications 22 35906200
2023 SERBP1 Promotes Stress Granule Clearance by Regulating 26S Proteasome Activity and G3BP1 Ubiquitination and Protects Male Germ Cells from Thermostimuli Damage. Research (Washington, D.C.) 21 37223481
2012 DISC1 conditioned GWAS for psychosis proneness in a large Finnish birth cohort. PloS one 20 22363459
2022 An epigenetic association analysis of childhood trauma in psychosis reveals possible overlap with methylation changes associated with PTSD. Translational psychiatry 19 35501310
2022 Proximity-dependent biotin identification (BioID) reveals a dynamic LSD1-CoREST interactome during embryonic stem cell differentiation. Molecular omics 15 34709266
2025 The solute carrier superfamily interactome. Molecular systems biology 9 40355756
2023 Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 8 37249750
2023 USP9X deubiquitinates and stabilizes CDC123 to promote breast carcinogenesis through regulating cell cycle. Molecular carcinogenesis 8 37314216
2023 Defining Distinct RNA-Protein Interactomes of SARS-CoV-2 Genomic and Subgenomic RNAs. Journal of proteome research 7 38043095
2024 TANGO6 regulates cell proliferation via COPI vesicle-mediated RPB2 nuclear entry. Nature communications 2 38490996
2025 Tango6 regulates HSPC proliferation and definitive haematopoiesis via Ikzf1 and Cmyb in caudal haematopoietic tissue. Development (Cambridge, England) 0 39620979