Evidence map›Paper›PMID 41075246›Full record

ArticleCell reports2025

HUWE1 stimulates mTORC1 activity by enhancing Rheb interaction with mTORC1 and supports de novo pyrimidine synthesis.

Takayuki Ikeda, Sungki Hong, Shota Yoshida, Swayam Prakash Srivastava, Abhiram Kunamneni, Yao Yao, Om Khuperkar, Venkatesha Basrur, Henry Kuang, Maureen Kachman and 11 more

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 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing 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

2 citing papers in PubMed.

  1. Article
  2. 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

21 authors.

Takayuki IkedaLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA; Department of Biochemistry, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan.
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.
Swayam Prakash SrivastavaLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA.
Abhiram KunamneniLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA.
Yao YaoLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA.
Om KhuperkarLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA.
Venkatesha BasrurDepartment of Pathology, University of Michigan, 2800 Plymouth Road, Bldg. 35, Ann Arbor, MI 48109-2800, USA.
Henry KuangLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA; Department of Cell & Developmental Biology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
Maureen KachmanBiomedical Research Core Facilities, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105-5714, USA.
Abraham RaskindBiomedical Research Core Facilities, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105-5714, USA.
Heidi BaumBiomedical Research Core Facilities, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105-5714, USA.
Arya JoshiLife 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.
Aaron ThurmanLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA.
Oliviamae Kopasz-GemmenLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA.
Siddharth KandukuriLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA.
F N U PradeepaLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA.
Hideto YonekuraDepartment of Biochemistry, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan.
Jiandie D LinLife Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA; Department of Cell & Developmental Biology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, 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 St., 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

The mechanistic target of rapamycin complex 1 (mTORC1), a central regulator of cell growth, is activated by Rheb small GTPase. Our recent studies have demonstrated that polyubiquitinated Rheb enhances its interaction with mTORC1, resulting in the activation of mTORC1. Here, we demonstrate that the HECT, UBA, and WWE domain containing E3 ubiquitin protein ligase 1 (HUWE1), an E3 ubiquitin ligase, preferentially interacts with ubiquitinated Rheb and facilitates Rheb's binding to mTORC1 and its subsequent activation. The ablation of HUWE1 results in reduced ubiquitination of Rheb and decreased mTORC1 activity in cultured cells and mouse liver. HUWE1 is also necessary for Rheb to interact with carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase (CAD), a key enzyme in pyrimidine biosynthesis, and for CAD activation through the activation of the mTORC1-S6K1 pathway. Moreover, HUWE1 maintains CAD expression by increasing its transcript in cells and liver tissues. Therefore, HUWE1 acts as a key organizer of the ubiquitinated Rheb complex, playing a vital role in enhancing mTORC1 activity and pyrimidine synthesis by increasing both CAD activity and expression.

Indexed as

Mechanistic Target of Rapamycin Complex 1Monomeric GTP-Binding ProteinsMultiprotein ComplexesPyrimidinesRas Homolog Enriched in Brain ProteinTOR Serine-Threonine KinasesTumor Suppressor ProteinsUbiquitin-Protein LigasesAnimalsCarbamoyl-Phosphate Synthase (Ammonia)HEK293 CellsHumansLiverMiceProtein BindingUbiquitinationCarbamoyl-Phosphate Synthase (Ammonia)HUWE1 protein, humanMechanistic Target of Rapamycin Complex 1Monomeric GTP-Binding ProteinsMultiprotein ComplexespyrimidinePyrimidinesRas Homolog Enriched in Brain ProteinRHEB protein, humanRheb protein, mouseTOR Serine-Threonine KinasesTumor Suppressor ProteinsUbiquitin-Protein LigasesCADCP: Cell biologyCP: Molecular biologyHUWE1mTORmTORC1pyrimidineRhebubiquitination

Identifiers

PMID41075246
PMCPMC12588189

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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.