Evidence map›Paper›PMID 39708321›Full record

ArticleCell reports2025

The Cullin3-Rbx1-KLHL9 E3 ubiquitin ligase complex ubiquitinates Rheb and supports amino acid-induced mTORC1 activation.

Yao Yao, Sungki Hong, Shota Yoshida, Vinamra Swaroop, Brady Curtin, Ken Inoki

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
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  3. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

6 authors.

Yao YaoLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA.
Sungki HongLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA.
Shota YoshidaLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA.
Vinamra SwaroopLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA.
Brady CurtinLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA.
Ken InokiLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical School, 1137 E. Catherine Streett, Ann Arbor, MI 48109-5622, USA; Department of Internal Medicine, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5368, USA. Electronic address: inokik@umich.edu.

Funding

Lysosomal cholesterol-dependent anabolic regulationR01DK124709 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI INOKI, KEN · 2022 to 2025
$2.1M
Molecular mechanism of Rheb-dependent mTORC1 regulationR01GM145631 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI INOKI, KEN · 2022 to 2025
$1.8M
NIDDK NIH HHS R01 DK124709NIGMS NIH HHS R01 GM145631
6 · The paper itself

Abstract

Mechanistic target of rapamycin complex 1 (mTORC1) is recruited to the lysosomal membrane by the active Rag heterodimer, where mTORC1 interacts with active Rheb for its activation. It has been shown that polyubiquitination of Rheb is crucial for enhancing its interaction with mTORC1 on the lysosome. However, the specific ubiquitin ligases for Rheb, which promotes mTORC1 activation, remain elusive. We report that the CUL3-RBX1-KLHL9 E3 ubiquitin ligase complex is translocated to the lysosome and ubiquitinates Rheb in response to amino acid stimulation. KLHL9 serves as an essential adaptor for CUL3-RBX1 to target Rheb on the lysosome. Deleting either CUL3, RBX1, or KLHL9 diminishes Rheb ubiquitination and reduces amino acid-induced mTORC1 activation without impacting lysosomal mTORC1 localization or Akt activity. Thus, the CUL3-RBX1-KLHL9 complex functions as a mTORC1 activator by acting as an E3 ubiquitin ligase for Rheb and supports amino acid-induced mTORC1 activation.

Indexed as

Adaptor Proteins, Signal TransducingAmino AcidsCarrier ProteinsCullin ProteinsMechanistic Target of Rapamycin Complex 1Ras Homolog Enriched in Brain ProteinUbiquitin-Protein LigasesAnimalsHEK293 CellsHumansLysosomesMiceUbiquitinationAdaptor Proteins, Signal TransducingAmino AcidsCarrier ProteinsCUL3 protein, humanCul3 protein, mouseCullin ProteinsMechanistic Target of Rapamycin Complex 1Ras Homolog Enriched in Brain ProteinRBX1 protein, humanUbiquitin-Protein LigasesCP: Cell biologyCUL3KLHL9lysosomemTORC1Rhebubiquitination

Identifiers

PMID39708321
PMCPMC11844325

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.