Affinage

HEATR1

HEAT repeat-containing protein 1 · UniProt Q9H583

Length
2144 aa
Mass
242.4 kDa
Annotated
2026-06-10
12 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HEATR1 is a conserved nucleolar protein required for ribosomal RNA transcription and early pre-rRNA processing, with a particular role in the maturation of 18S rRNA (PMID:16531401, PMID:17652137, PMID:29143558). Studies of its yeast (Utp10) and zebrafish (Bap28) orthologs established that it co-precipitates with U3 snoRNA and early pre-rRNA processing intermediates, and that its specific loss blocks early processing steps for 18S rRNA without affecting transcription or large-subunit rRNA synthesis (PMID:17652137). In human cells HEATR1 positively regulates rRNA synthesis and maintains nucleolar integrity; its depletion disrupts nucleolar structure and activates the RPL5/RPL11–MDM2–p53 ribosome biogenesis stress checkpoint, driving p53-dependent cell cycle arrest (PMID:29143558), apoptosis through PUMA/BAX induction and BCL2 repression (PMID:31190896), or ferroptosis via a p53/SAT1/ALOX15 axis (PMID:38818906). Beyond rRNA synthesis itself, HEATR1 supports ribogenesis through additional partners: it binds the Pontin/Reptin AAA+ ATPase complex, stabilizing it to promote mTOR signalling and pre-rRNA synthesis (PMID:33894417), and it binds MYC to promote MYC's nucleolar localization and MYC-driven rRNA generation (PMID:38225354). HEATR1 also acts as a cytoplasmic scaffold outside ribosome biogenesis: it bridges AKT to the phosphatase PP2A to promote AKT dephosphorylation at Thr308 (PMID:26676747), and competes with Keap1 for binding to p62/SQSTM1 to modulate Nrf2 signalling (PMID:31785531); loss of these functions confers gemcitabine resistance in pancreatic cancer cells (PMID:26676747, PMID:31785531).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2006 High

    Establishing that the HEATR1 ortholog is required for rRNA biogenesis and acts upstream of p53-mediated apoptosis answered whether the protein's developmental phenotype reflects a ribosome biogenesis stress response.

    Evidence Positional cloning and genetic epistasis (bap28 mutant × p53 morpholino) with rRNA processing assays in zebrafish

    PMID:16531401

    Open questions at the time
    • Did not define the molecular machinery HEATR1 acts within
    • Mechanism by which loss is sensed to activate p53 not resolved in this system
  2. 2007 High

    Identifying the yeast ortholog Utp10 as a U3 snoRNP/pre-rRNA-associated factor specified that HEATR1 functions in early processing steps for 18S rRNA rather than in transcription or large-subunit synthesis.

    Evidence Co-precipitation with U3 snoRNA and pre-rRNA, genetic depletion, Northern blot of rRNA intermediates, epistasis with TRAMP5/exosome surveillance

    PMID:17652137

    Open questions at the time
    • Direct binding partners within the processome not enumerated
    • Structural basis of U3 snoRNP association unknown
  3. 2015 Medium

    Discovery of a scaffold role bridging AKT and PP2A established a nucleolus-independent function for HEATR1 in growth-factor signalling and chemoresistance.

    Evidence Co-IP of HEATR1–AKT–PP2A, pAKT-Thr308 Western blot, HEATR1 silencing with chemosensitivity readout and AKT-inhibitor rescue in pancreatic cancer cells

    PMID:26676747

    Open questions at the time
    • Single lab
    • Whether scaffold function is direct or requires additional adaptors not resolved
    • Relationship to nucleolar HEATR1 pool unclear
  4. 2017 High

    Direct demonstration in human cells that HEATR1 is nucleolar and that its loss activates the RPL5/RPL11–MDM2–p53 checkpoint placed the mammalian protein firmly in the ribosome biogenesis stress pathway.

    Evidence HEATR1 knockdown, nucleolar imaging, cell cycle flow cytometry, Western blot for p53/MDM2/RPL5/RPL11, rRNA synthesis assays

    PMID:29143558

    Open questions at the time
    • Did not identify HEATR1's binding partners in human processome
    • Quantitative contribution to rRNA transcription vs processing not separated
  5. 2019 Medium

    Defining the downstream effectors (PUMA/BAX up, BCL2 down) and confirming p53 dependence by double knockdown clarified how HEATR1 loss is executed as apoptosis.

    Evidence shRNA knockdown of HEATR1 ± p53, Western blot/qRT-PCR for p53/PUMA/BAX/BCL2, proliferation/apoptosis assays, xenograft and microarray in NSCLC

    PMID:31190896

    Open questions at the time
    • Single lab
    • p53-independent contributions not addressed
  6. 2019 Medium

    Identifying competitive binding between HEATR1 and Keap1 for p62/SQSTM1 added a second cytoplasmic role linking HEATR1 to Nrf2-mediated redox and chemoresistance.

    Evidence Co-IP competition assays, HEATR1 knockdown, Nrf2-pathway Western blot, xenograft models in pancreatic cancer

    PMID:31785531

    Open questions at the time
    • Single lab
    • Stoichiometry of HEATR1/Keap1/p62 competition not quantified
    • Interplay with nucleolar function unclear
  7. 2021 Medium

    Showing HEATR1 binds and stabilizes the Pontin/Reptin complex connected its scaffold activity to mTOR signalling and pre-rRNA synthesis in tumour proliferation.

    Evidence Co-IP, protein stability assays, pre-rRNA synthesis assay, mTOR Western blot, HEATR1 knockdown proliferation readout in OSCC

    PMID:33894417

    Open questions at the time
    • Single lab
    • Direct vs indirect stabilization mechanism not resolved
    • Whether mTOR effect is upstream or downstream of rRNA changes unclear
  8. 2024 Medium

    Demonstrating a HEATR1–MYC interaction that drives MYC nucleolar localization and MYC-dependent rRNA generation linked HEATR1 to oncogenic growth control in tumour-initiating cells.

    Evidence Co-IP/binding assay, fluorescence imaging of MYC localization, rRNA synthesis assays in Drosophila brat model and human glioblastoma stem cells

    PMID:38225354

    Open questions at the time
    • Single lab
    • Whether binding is direct and the interaction interface unknown
    • Generalizability beyond tumour-initiating cells not established
  9. 2025 Medium

    Placing HEATR1 upstream of a p53/SAT1/ALOX15 ferroptosis axis extended the consequences of HEATR1 loss beyond classical apoptosis in drug-resistant cells.

    Evidence shRNA knockdown of HEATR1 ± p53 ± ALOX15 genetic epistasis, lipid ROS flow cytometry, proliferation assays, xenograft in cisplatin-resistant NSCLC

    PMID:38818906

    Open questions at the time
    • Single lab
    • How ribosome stress selects ferroptosis vs apoptosis output not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HEATR1's distinct nucleolar (processome) and cytoplasmic scaffold (AKT/PP2A, p62/Keap1) functions are coordinated, and the structural basis of its partner interactions, remains unresolved.
  • No structural model of HEATR1 in the small subunit processome
  • Direct vs scaffold-mediated nature of most partner interactions undetermined
  • Whether cytoplasmic functions are separable from ribosome biogenesis is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0003723 RNA binding 1
Localization
GO:0005730 nucleolus 2
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-162582 Signal Transduction 2 R-HSA-5357801 Programmed Cell Death 2
Partners
AKTKEAP1MYCPP2ARUVBL1RUVBL2SQSTM1
Complex memberships
small subunit (SSU) processome / U3 snoRNP

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Zebrafish Bap28 (ortholog of human HEATR1/BAP28) is required for rRNA transcription and processing, with a major effect on 18S rRNA maturation; genetic loss-of-function causes excess apoptosis in the CNS, and inhibition of p53 rescues the morphological defects, placing Bap28 upstream of p53-mediated apoptosis in a ribosome biogenesis stress pathway. Positional cloning, genetic epistasis (bap28 mutant × p53 morpholino knockdown), rRNA processing assays in zebrafish The Journal of biological chemistry High 16531401
2007 Yeast Utp10 (ortholog of HEATR1) co-precipitates with U3 snoRNA and early pre-rRNA processing intermediates; genetic depletion specifically inhibits early pre-rRNA processing steps required for 18S rRNA maturation without affecting pre-rRNA transcription or 25S/5.8S synthesis; aberrant 23S RNA accumulates and is normally degraded by the TRAMP5/exosome surveillance pathway. Co-precipitation (coprecipitation with U3 snoRNA and pre-rRNA), genetic depletion, Northern blot analysis of rRNA intermediates, epistasis with poly(A) polymerase Trf5 deletion RNA (New York, N.Y.) High 17652137
2015 HEATR1 acts as a scaffold protein that facilitates physical interaction between AKT and the protein phosphatase PP2A, thereby promoting dephosphorylation of AKT at Thr308; loss of HEATR1 increases AKT Thr308 phosphorylation and confers chemoresistance to gemcitabine in pancreatic cancer cells. Co-immunoprecipitation (HEATR1–AKT–PP2A interaction), phosphorylation assays (Western blot for pAKT-Thr308), HEATR1 silencing with functional chemosensitivity readout, pharmacological AKT inhibitor rescue (triciribine) Cancer research Medium 26676747
2017 Human HEATR1 is a nucleolar protein that positively regulates rRNA synthesis; its depletion disrupts nucleolar structure and activates the RPL5/RPL11–MDM2–p53 ribosome biogenesis stress checkpoint, leading to p53-dependent cell cycle arrest. HEATR1 knockdown in human cells, nucleolar morphology imaging, flow cytometry (cell cycle), Western blot for p53/MDM2/RPL5/RPL11, rRNA synthesis assays Cell cycle (Georgetown, Tex.) High 29143558
2019 HEATR1 competes with Keap1 for binding to p62/SQSTM1; HEATR1 binding to p62 increases free Keap1 levels, which then suppresses Nrf2 signaling; HEATR1 knockdown reduces Keap1 availability, activates Nrf2, and promotes gemcitabine resistance in pancreatic cancer cells. Co-immunoprecipitation (HEATR1–p62 and Keap1–p62 competitive binding), HEATR1 knockdown, Western blot for Nrf2 pathway components, xenograft tumor models Redox biology Medium 31785531
2019 HEATR1 inhibition in non-small cell lung cancer activates p53 through reduced ribosome biogenesis, leading to upregulation of PUMA and BAX and downregulation of BCL2, causing apoptosis; double knockdown of HEATR1 and p53 rescues the proliferative phenotype, establishing p53 as the mediator of HEATR1 loss-of-function effects. shRNA knockdown of HEATR1 ± p53, Western blot and qRT-PCR for p53/PUMA/BAX/BCL2, cell proliferation and apoptosis assays, xenograft mouse model, microarray pathway analysis OncoTargets and therapy Medium 31190896
2021 HEATR1 physically interacts with the Pontin/Reptin AAA+ ATPase complex, stabilizes Pontin/Reptin protein levels, and through this interaction positively regulates mTOR signaling and pre-rRNA synthesis to promote oral squamous cell carcinoma cell proliferation. Co-immunoprecipitation identifying HEATR1 as Pontin/Reptin binding partner, protein stability assays, pre-rRNA synthesis assay, mTOR pathway Western blot, HEATR1 knockdown with proliferation readout Biochemical and biophysical research communications Medium 33894417
2024 HEATR1 physically binds the master growth regulator MYC, promotes MYC's nucleolar localization, and is required for MYC-driven ribosomal RNA generation and tumourigenic potential in brain tumour-initiating cells (Drosophila brat model and human glioblastoma stem cells). Co-immunoprecipitation/binding assay (HEATR1–MYC interaction), fluorescence imaging of MYC nucleolar localization, rRNA synthesis assays, Drosophila genetic model, patient-derived glioblastoma stem cell knockdown EMBO reports Medium 38225354
2025 HEATR1 silencing induces ferroptosis in cisplatin-resistant NSCLC cells via activation of the p53/SAT1/ALOX15 axis; p53 and ALOX15 silencing reverses ferroptosis and rescues the effects of HEATR1 knockdown, placing HEATR1 upstream of this ferroptosis pathway. shRNA knockdown of HEATR1 ± p53 ± ALOX15 (genetic epistasis), flow cytometry (lipid ROS, apoptosis), CCK-8 proliferation assay, Western blot and qRT-PCR for pathway components, xenograft mouse model Current cancer drug targets Medium 38818906

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Perturbation of rRNA synthesis in the bap28 mutation leads to apoptosis mediated by p53 in the zebrafish central nervous system. The Journal of biological chemistry 73 16531401
2007 Roles of the HEAT repeat proteins Utp10 and Utp20 in 40S ribosome maturation. RNA (New York, N.Y.) 43 17652137
2017 Perturbation of RNA Polymerase I transcription machinery by ablation of HEATR1 triggers the RPL5/RPL11-MDM2-p53 ribosome biogenesis stress checkpoint pathway in human cells. Cell cycle (Georgetown, Tex.) 35 29143558
2015 HEATR1 Negatively Regulates Akt to Help Sensitize Pancreatic Cancer Cells to Chemotherapy. Cancer research 34 26676747
2019 HEATR1 deficiency promotes pancreatic cancer proliferation and gemcitabine resistance by up-regulating Nrf2 signaling. Redox biology 32 31785531
2014 Glioma-associated antigen HEATR1 induces functional cytotoxic T lymphocytes in patients with glioma. Journal of immunology research 27 25126583
2019 HEATR1 modulates cell survival in non-small cell lung cancer via activation of the p53/PUMA signaling pathway. OncoTargets and therapy 13 31190896
2020 HEATR1 Deficiency Promotes Chemoresistance via Upregulating ZNF185 and Downregulating SMAD4 in Pancreatic Cancer. Journal of oncology 11 32565799
2021 HEATR1, a novel interactor of Pontin/Reptin, stabilizes Pontin/Reptin and promotes cell proliferation of oral squamous cell carcinoma. Biochemical and biophysical research communications 9 33894417
2020 HEATR1 promotes proliferation in gastric cancer in vitro and in vivo. Acta biochimica et biophysica Sinica 8 32634230
2025 Silencing HEATR1 Rescues Cisplatin Resistance of Non-small Cell Lung Cancer by Inducing Ferroptosis via the p53/SAT1/ALOX15 Axis. Current cancer drug targets 6 38818906
2024 Ribogenesis boosts controlled by HEATR1-MYC interplay promote transition into brain tumour growth. EMBO reports 5 38225354

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