Affinage

RHEBL1

GTPase RhebL1 · UniProt Q8TAI7

Length
183 aa
Mass
20.7 kDa
Annotated
2026-06-10
25 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RHEBL1 (RhebL1/Rheb2) is a ubiquitously expressed small GTPase of the Rheb branch that functions as a GTP-dependent signaling switch upstream of mTORC1 and additional growth and stress pathways (PMID:16098514, PMID:16328882). Its activation of mTOR depends on switch I (N41) and effector-domain (Y/F54, L56) residues, with N41 specifically required for direct mTOR binding, and is negatively regulated by the TSC1/TSC2 complex and by FKBP38 (PMID:16098514, PMID:19272448). RHEBL1 signaling requires intrinsic G-protein activity, demonstrated by the constitutively active Q64L and dominant-negative D60K mutants across multiple effector readouts (PMID:16328882, PMID:28209923). Beyond mTORC1, GTP- and effector-domain-dependent binding directs RhebL1 to additional effectors: it binds and stimulates the carbamoyl-phosphate synthetase activity of CAD to support pyrimidine biosynthesis (PMID:25422319), and binds and activates AKT1 to drive keratin 8 phosphorylation, cytoskeletal reorganization, and cancer cell migration and invasion (PMID:28209923). RHEBL1 expression is transcriptionally induced by the TAZ/TEAD axis, and this TAZ–RhebL1–mTOR–TFAM circuit drives mitochondrial biogenesis and protects skeletal muscle from atrophy in vivo (PMID:35115527, PMID:40159627). RHEBL1 acts as a negative regulator of autophagy and mitophagy and is itself subject to epigenetic control, with miR-138-5p promoting its expression by suppressing DNMT3A-mediated promoter methylation (PMID:39122135, PMID:40121052). It additionally restricts influenza A virus replication in human alveolar epithelial cells (PMID:38538289).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2005 High

    Established that RHEBL1 is a functional Rheb-branch GTPase that directly engages and activates mTOR, defining its core signaling identity and placing it under TSC1/TSC2 control.

    Evidence Overexpression/mutagenesis with co-immunoprecipitation for mTOR binding and mTOR signaling readouts during nutrient withdrawal in cell lines

    PMID:16098514

    Open questions at the time
    • No structural model of the RhebL1–mTOR interface
    • Endogenous (vs overexpressed) contribution to mTORC1 not addressed
    • GAP/GEF regulators of the GTPase cycle not defined here
  2. 2005 Medium

    Showed RHEBL1 activity extends beyond mTOR to NF-κB transcriptional activation in a G-protein-dependent manner, broadening its effector scope.

    Evidence Subcellular localization in COS7 cells and NF-κB reporter assays in HEK293T with wild-type and GTPase-deficient D60K mutant

    PMID:16328882

    Open questions at the time
    • Direct NF-κB pathway effector not identified
    • Reporter assay without endogenous loss-of-function confirmation
    • Localization assessed only under overexpression
  3. 2009 Medium

    Placed RhebL1 upstream of mTORC1 as a target of negative regulation by FKBP38, refining the regulatory architecture of its mTOR activation.

    Evidence In vitro mTORC1 kinase assay with overexpressed RhebL1 and FKBP38

    PMID:19272448

    Open questions at the time
    • Finding incidental to a study of other mTORC1 components
    • FKBP38–RhebL1 direct binding not mapped
    • No in vivo validation
  4. 2011 Medium

    Demonstrated that RhebL1 and Rheb1 are functionally non-redundant, since RhebL1 silencing does not reduce S6 phosphorylation, indicating distinct routes into the mTOR pathway.

    Evidence siRNA knockdown of Rheb1 and RhebL1 with phospho-S6 Western blots across HEK293, HeLa, and NIH3T3

    PMID:21655954

    Open questions at the time
    • Does not explain why overexpressed RhebL1 activates mTOR but knockdown has no effect
    • Cell-type or context dependence of the negative result unresolved
    • Effectors mediating the RhebL1-specific output not identified
  5. 2014 High

    Identified CAD as a direct RhebL1 effector, linking RhebL1 GTPase activity to stimulation of pyrimidine biosynthesis independent of mTOR.

    Evidence Co-IP/pulldown, deletion-construct domain mapping, in vitro CPSase enzymatic assay, and CAD immunostaining

    PMID:25422319

    Open questions at the time
    • Cellular consequence of CAD activation for nucleotide pools not quantified
    • Whether this pathway operates in vivo unaddressed
    • Relationship to mTOR-dependent CAD regulation not resolved
  6. 2017 Medium

    Showed RhebL1 binds and activates AKT1 in a G-protein-dependent manner, coupling it to keratin 8 reorganization and cancer cell migration/invasion.

    Evidence Co-IP, Q64L/D60K mutant analysis, siRNA knockdown, and MK2206 AKT inhibition in A549 cells

    PMID:28209923

    Open questions at the time
    • Whether AKT1 binding is direct or via an intermediary not resolved
    • Single cell line/single lab
    • Mechanism linking AKT1 to keratin 8 phosphorylation not detailed
  7. 2020 Low

    Synthesized membrane-targeting mechanism for RhebL1, attributing its weak membrane association to C-terminal farnesylation and a PDEδ/Arl2 interaction.

    Evidence Mechanistic review synthesizing prior farnesylation-mutant and PDEδ interaction data

    PMID:32518628

    Open questions at the time
    • Review without new primary RhebL1 experiments
    • Quantitative membrane partitioning not established
    • Functional consequence of PDEδ binding for signaling untested
  8. 2021 Medium

    Identified SmgGDS as a binding partner that retains GDP-bound RhebL1 in the cytosol, and confirmed RhebL1 as a pro-oncogenic mTORC1 activator.

    Evidence Protein binding assays, siRNA knockdown, mTORC1 marker Western blots, proliferation assays, and TCGA analysis in mesothelioma cells

    PMID:33574130

    Open questions at the time
    • Structural basis of preferential GDP-state binding unknown
    • Whether SmgGDS acts as GDI/GEF for RhebL1 not resolved
    • Single lab
  9. 2022 High

    Established a TAZ/TEAD→RhebL1→mTOR→TFAM circuit driving mitochondrial biogenesis, providing the first in vivo genetic placement of RhebL1.

    Evidence Muscle-specific TAZ-knockout mice with AAV-Rhebl1 rescue, mitochondrial biogenesis/respiration assays, and exercise testing

    PMID:35115527

    Open questions at the time
    • Mechanism by which mTOR selectively boosts TFAM translation not detailed
    • Tissue specificity beyond muscle untested
    • Direct TEAD occupancy of the RHEBL1 promoter not mapped here
  10. 2023 Low

    Placed RHEBL1 as an upstream activator of the TBK1–IRF3 innate immune axis, extending its effector range to antiviral signaling.

    Evidence Constitutively active small-GTPase library screen with IRF3 phosphorylation readouts and TBK1-dependence testing

    PMID:36579460

    Open questions at the time
    • RHEBL1 one of many screen hits without dedicated follow-up
    • Direct vs indirect TBK1 activation unresolved
    • Endogenous loss-of-function not tested
  11. 2024 Medium

    Defined epigenetic control of RHEBL1, with miR-138-5p suppressing DNMT3A to demethylate the Rhebl1 promoter and enhance ubiquitin-dependent mitophagy in hypoxic neurons.

    Evidence miRNA gain/loss, DNMT3A knockdown, LC3/RHEBL1 Western blots, and mitophagy assays in OGD/R neurons

    PMID:39122135

    Open questions at the time
    • Direct demethylation of the RHEBL1 promoter vs indirect effect not fully separated
    • How RhebL1 promotes mitophagy mechanistically unclear
    • Single lab/system
  12. 2024 Medium

    Showed endogenous RhebL1 acts as a host restriction factor against influenza A replication in human alveolar epithelial cells.

    Evidence siRNA knockdown with viral nucleoprotein/cytokeratin 8 immunofluorescence and TCID50 yield assays in A549 vs LLC-MK2 cells

    PMID:38538289

    Open questions at the time
    • Molecular mechanism of restriction not defined
    • Host-species dependence (A549 vs LLC-MK2) unexplained
    • Link to RhebL1 signaling effectors not established
  13. 2025 Low

    Implicated RhebL1 as a negative regulator of autophagy in cardiac fibroblasts, downregulated by senescent EV-delivered miRNAs.

    Evidence EV miRNA-seq with LC3-II/LC3-I Western blots and siRNA Rhebl1 knockdown in neonatal rat cardiac fibroblasts

    PMID:40121052

    Open questions at the time
    • siRNA autophagy effect only tendential, not statistically robust
    • Effector pathway from RhebL1 to autophagy machinery unidentified
    • Single lab/system
  14. 2025 Medium

    Demonstrated that stabilized TAZ induces RhebL1 to sustain mTOR signaling and protect against dexamethasone-induced muscle atrophy, with Atrogin-1/MuRF1 degrading TAZ to suppress this axis.

    Evidence AAV TAZ-mutant overexpression in mice, Co-IP of TAZ with Atrogin-1/MuRF1, and atrophy models in C2C12 and mouse muscle

    PMID:40159627

    Open questions at the time
    • Whether Atrogin-1/MuRF1 ubiquitinate TAZ directly not fully shown
    • RhebL1's contribution vs other TAZ targets in atrophy not isolated
    • Therapeutic relevance untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RHEBL1 selects among its many reported effectors (mTORC1, AKT1, CAD, NF-κB, TBK1) in a given cell context, and what GEFs/GAPs control its GTPase cycle, remains unresolved.
  • No defined GEF/GAP for RhebL1
  • No structural basis for effector selectivity
  • Reconciliation of overexpression activation vs knockdown null phenotypes outstanding

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-9612973 Autophagy 2 R-HSA-1430728 Metabolism 1 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
AKT1CADFKBP38MTORPDE6DSMGGDS

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 RhebL1 (RHEBL1) rescues mTOR signaling during nutrient withdrawal, and TSC1/TSC2 impairs RhebL1-mediated mTOR signaling. Critical residues in the switch I region (N41) and constitutive effector (Ec) region (Y/F54 and L56) are required for efficient mTOR activation. Mutation of N41 impairs RhebL1 interaction with mTOR, identifying mTOR as a direct downstream target of RhebL1. Overexpression/mutagenesis in cell lines, co-immunoprecipitation to assess mTOR binding FEBS letters High 16098514
2005 RHEBL1 encodes a 183-amino-acid small GTPase of the Rheb branch, is ubiquitously expressed, localizes to the cytoplasm when overexpressed in COS7 cells, and activates NF-κB transcriptional activity. The GTPase-deficient mutant D60K only weakly activates NF-κB, indicating that G-protein activity is required. Subcellular localization by fluorescence/overexpression in COS7 cells; NF-κB reporter gene assay in HEK293T cells with wild-type and D60K mutant RHEBL1 Molecular biology reports Medium 16328882
2009 Activation of mTORC1 by RhebL1 is impaired by FKBP38, as shown in an in vitro mTORC1 kinase assay, placing RhebL1 upstream of mTORC1 and subject to negative regulation by FKBP38. In vitro mTORC1 kinase assay with overexpressed RhebL1 and FKBP38 Cellular signalling Medium 19272448
2011 RhebL1 silencing (by siRNA) does not affect phosphorylation of the mTOR effector S6 in HEK293, HeLa, or NIH3T3 cells, in contrast to Rheb1 silencing which reduces S6 phosphorylation, suggesting RhebL1 impacts the mTOR pathway differently from Rheb1 (negative/distinct result). siRNA knockdown of Rheb1 and RhebL1 individually and in combination in three cell lines; Western blot for phospho-S6 Molecular biology reports Medium 21655954
2014 RhebL1 (referred to as Rheb2) binds CAD (carbamoyl-phosphate synthetase 2/aspartate transcarbamoylase/dihydroorotase) in a GTP- and effector domain-dependent manner, more strongly than Rheb1 does. The binding region on CAD maps to the C-terminal region of its carbamoyl-phosphate synthetase domain. RhebL1/Rheb stimulates CAD's carbamoyl-phosphate synthetase activity in vitro. Co-immunoprecipitation/pulldown to identify binding; in vitro enzymatic assay for CPSase activity; domain mapping by deletion constructs; immunostaining for CAD localization The Journal of biological chemistry High 25422319
2017 RhebL1 binds and activates AKT1, and its G-protein activity (shown with constitutively active Q64L and dominant-negative D60K mutants) is required for AKT1 binding and activation, leading to keratin 8 phosphorylation, reorganization, and increased cell migration and invasion in sphingosylphosphorylcholine-treated cancer cells. Co-immunoprecipitation of RhebL1 with AKT1; constitutively active (Q64L) and dominant-negative (D60K) mutant analysis; siRNA knockdown; AKT inhibitor (MK2206) treatment; overexpression experiments in A549 cells Oncotarget Medium 28209923
2020 RhebL1 undergoes C-terminal farnesylation that confers weak membrane interactions sufficient for mTORC1 activation, and also mediates an interaction with PDEδ (phosphodiesterase 6 δ subunit), which together with Arl2 provides a potential membrane-targeting mechanism. This minimal membrane targeting distinguishes RhebL1 from other Ras superfamily members. Review/synthesis with experimental context from prior studies; farnesylation mutant analyses and PDEδ interaction data reviewed from existing literature F1000Research Low 32518628
2021 SmgGDS is a novel RhebL1-binding protein with high binding affinity for inactive GDP-bound RhebL1. SmgGDS knockdown reduces cytosolic RhebL1 levels without affecting its activation state, suggesting SmgGDS retains GDP-bound RhebL1 in the cytosol. Exogenous RHEBL1 expression enhances mesothelioma cell growth, confirming RhebL1 as a pro-oncogenic activator of mTORC1. Protein binding assays (SmgGDS–RHEBL1 interaction); siRNA knockdown; Western blot for mTORC1 activation markers; cell proliferation assays; analysis of TCGA expression data Molecular cancer research : MCR Medium 33574130
2022 TAZ (transcriptional coactivator with PDZ-binding motif) stimulates RhebL1 expression via TEAD transcription factors, and RhebL1 in turn activates mTOR to promote translation of mitochondrial transcription factor A (TFAM), thereby driving mitochondrial biogenesis. Adeno-associated virus-mediated Rhebl1 introduction rescued mitochondrial biogenesis in muscle-specific TAZ-knockout mice. Muscle-specific TAZ-knockout mice; AAV-mediated Rhebl1 rescue; qRT-PCR and Western blot for mTOR signaling; mitochondrial biogenesis and respiration assays; exercise performance testing Nature communications High 35115527
2023 Constitutively active RHEBL1 (among 27 of 152 small GTPases screened) promotes IRF3 phosphorylation in a TBK1-dependent manner, placing RHEBL1 as an upstream activator of the TBK1–IRF3 innate immune signaling axis. Constitutively active mutant library screen; reporter/Western blot for IRF3 phosphorylation; TBK1 dependence validated by co-expression/inhibition Biomolecules & therapeutics Low 36579460
2024 miR-138-5p promotes stable expression of RHEBL1 through suppression of DNMT3A (reducing Rhebl1 promoter methylation), thereby enhancing ubiquitin-dependent mitophagy and maintaining mitochondrial homeostasis in hypoxia-injured neurons. miRNA overexpression/inhibition; DNMT3A knockdown; Western blot for RHEBL1 and autophagy markers (LC3); functional mitophagy and mitochondrial function assays in OGD/R-injured neurons Acta biomaterialia Medium 39122135
2025 Senescent cardiac fibroblast-derived extracellular vesicles (containing upregulated miRNAs) decrease RHEBL1 protein expression in recipient cardiac fibroblasts, leading to increased autophagy (elevated LC3-II/LC3-I ratio). siRNA knockdown of Rhebl1 tendentially increased LC3-II/LC3-I, supporting RHEBL1 as a negative regulator of autophagy in cardiac fibroblasts. miRNA-seq of EV; Western blot for RHEBL1 and LC3-II/LC3-I; siRNA knockdown of Rhebl1 in neonatal rat cardiac fibroblasts Journal of pharmacological sciences Low 40121052
2025 TAZ mutant (resistant to proteolytic degradation) stimulates mTOR signaling and inhibits dexamethasone-induced muscle atrophy via induction of RhebL1. Atrogin-1 and MuRF1 interact with TAZ and facilitate its degradation, thereby reducing RhebL1 expression and mTOR signaling during dexamethasone treatment. AAV-mediated overexpression of TAZ mutant in mice; Western blot and qRT-PCR for RhebL1 and mTOR signaling markers; co-immunoprecipitation of TAZ with Atrogin-1/MuRF1; C2C12 myotube and mouse muscle atrophy models Journal of cachexia, sarcopenia and muscle Medium 40159627
2024 RhebL1 silencing in A549 human alveolar epithelial cells (but not LLC-MK2 rhesus monkey kidney cells) increases influenza A/NWS/33 virus replication and expression of hyperphosphorylated cytokeratin 8 (a marker of viral infection efficiency), indicating that endogenous RhebL1 acts as a host cell-dependent restrictive factor against influenza virus replication. siRNA knockdown of RhebL1; indirect immunofluorescence for viral nucleoprotein and cytokeratin 8; TCID50 viral yield assay in A549 and LLC-MK2 cells Frontiers in bioscience (Landmark edition) Medium 38538289

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Activation of the mTOR signaling pathway in renal clear cell carcinoma. The Journal of urology 145 17162089
2020 Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex. Cell reports 114 32268104
2012 Replication of bipolar disorder susceptibility alleles and identification of two novel genome-wide significant associations in a new bipolar disorder case-control sample. Molecular psychiatry 107 23070075
2005 Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1. FEBS letters 85 16098514
2009 Mammalian target of rapamycin complex 1-mediated phosphorylation of eukaryotic initiation factor 4E-binding protein 1 requires multiple protein-protein interactions for substrate recognition. Cellular signalling 65 19272448
2021 Novel Risk Loci Associated With Genetic Risk for Bipolar Disorder Among Han Chinese Individuals: A Genome-Wide Association Study and Meta-analysis. JAMA psychiatry 51 33263727
2018 Long-lived rodents reveal signatures of positive selection in genes associated with lifespan. PLoS genetics 47 29570707
2017 TIM-3 Engagement Promotes Effector Memory T Cell Differentiation of Human Antigen-Specific CD8 T Cells by Activating mTORC1. Journal of immunology (Baltimore, Md. : 1950) 36 29127145
2022 TAZ links exercise to mitochondrial biogenesis via mitochondrial transcription factor A. Nature communications 31 35115527
2020 Coordination of Rheb lysosomal membrane interactions with mTORC1 activation. F1000Research 31 32518628
2014 Rheb protein binds CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase) protein in a GTP- and effector domain-dependent manner and influences its cellular localization and carbamoyl-phosphate synthetase (CPSase) activity. The Journal of biological chemistry 24 25422319
2006 Frequent [corrected] hyperphosphorylation of ribosomal protein S6 [corrected] in lymphangioleiomyomatosis-associated angiomyolipomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 24 16575396
2005 Identification and characterization of RHEBL1, a novel member of Ras family, which activates transcriptional activities of NF-kappa B. Molecular biology reports 23 16328882
2013 DHH-RHEBL1 fusion transcript: a novel recurrent feature in the new landscape of pediatric CBFA2T3-GLIS2-positive acute myeloid leukemia. Oncotarget 18 24127550
2024 An engineered cellular carrier delivers miR-138-5p to enhance mitophagy and protect hypoxic-injured neurons via the DNMT3A/Rhebl1 axis. Acta biomaterialia 17 39122135
2023 Establishing a prediction model of severe acute mountain sickness using machine learning of support vector machine recursive feature elimination. Scientific reports 14 36944699
2011 Effects of RhebL1 silencing on the mTOR pathway. Molecular biology reports 11 21655954
2022 Genome-Wide Association Analysis of Over 170,000 Individuals from the UK Biobank Identifies Seven Loci Associated with Dietary Approaches to Stop Hypertension (DASH) Diet. Nutrients 9 36297114
2017 Novel involvement of RhebL1 in sphingosylphosphorylcholine-induced keratin phosphorylation and reorganization: Binding to and activation of AKT1. Oncotarget 9 28209923
2022 Machine learning and bioinformatics-based insights into the potential targets of saponins in Paris polyphylla smith against non-small cell lung cancer. Frontiers in genetics 6 36386821
2021 Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation. Molecular cancer research : MCR 5 33574130
2023 Identification of Small GTPases That Phosphorylate IRF3 through TBK1 Activation Using an Active Mutant Library Screen. Biomolecules & therapeutics 4 36579460
2025 Transcriptional Co-Activator With PDZ Binding Motif (TAZ) Inhibits Dexamethasone-Induced Muscle Atrophy via mTOR Signalling. Journal of cachexia, sarcopenia and muscle 3 40159627
2025 Senescent cardiac fibroblasts-derived extracellular vesicles induced autophagy in cardiac fibroblasts via suppression of ras homolog enriched in brain like 1. Journal of pharmacological sciences 2 40121052
2024 Host Cell-dependent Modulatory Role of Ras Homolog Enriched in Brain-Like-1 (RhebL1) Protein in Influenza A/NWS/33 Virus-infected Mammalian Cells. Frontiers in bioscience (Landmark edition) 0 38538289

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