Evidence map›Paper›PMID 38746323›Full record

ArticleResearch square2024

The CTLH Ubiquitin Ligase Substrates ZMYND19 and MKLN1 Negatively Regulate mTORC1 at the Lysosomal Membrane.

Yin Wang, Rui Guo, Brenda Iturbide Piedras, Hsin-Yao Tang, John M Asara, Italo Tempera, Paul M Lieberman, Benjamin E Gewurz

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PubMed Full text at PMC Publisher
In one paragraph

Article in Research square, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

8 authors.

Yin WangDivision of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.ORCID 0000-0002-8137-7496
Rui GuoDivision of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.ORCID 0000-0003-4584-1324
Brenda Iturbide PiedrasDivision of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Hsin-Yao TangThe Wistar Institute, Philadelphia, PA, USA.ORCID 0000-0003-1838-018X
John M AsaraDivision of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.
Italo TemperaThe Wistar Institute, Philadelphia, PA, USA.
Paul M LiebermanThe Wistar Institute, Philadelphia, PA, USA.
Benjamin E GewurzDivision of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Program in Virology, Harvard Medical School.ORCID 0000-0002-3965-3418

Funding

Tumor Microenvironment and MetastasisP30CA010815 · NCI · WISTAR INSTITUTE · PI Aaron Robert Goldman · 1985 to 2026
$75.9M
Targeting the Epigenetic and Metabolic Control of EBV-Epithelial CancersP01CA269043 · NCI · WISTAR INSTITUTE · PI Italo Tempera · 2023 to 2026
$12.0M
Advancing Cancer Research through Comprehensive Proteomics and Metabolomics AnalysesR50CA221838 · NCI · WISTAR INSTITUTE · PI Hsin-Yao Tang · 2017 to 2026
$2.1M
Exploiting Metabolism to Uncloak Epstein-Barr Virus Immunogens in Latently Infected B-cellsR00DE031016 · NIDCR · TUFTS UNIVERSITY BOSTON · PI GUO, RUI · 2023 to 2025
$747k
NCI NIH HHS P01 CA269043NCI NIH HHS P30 CA010815NCI NIH HHS R50 CA221838NIDCR NIH HHS R00 DE031016
6 · The paper itself

Abstract

Most Epstein-Barr virus-associated gastric carcinoma (EBVaGC) harbor non-silent mutations that activate phosphoinositide 3 kinase (PI3K) to drive downstream metabolic signaling. To gain insights into PI3K/mTOR pathway dysregulation in this context, we performed a human genome-wide CRISPR/Cas9 screen for hits that synergistically blocked EBVaGC proliferation together with the PI3K antagonist alpelisib. Multiple subunits of carboxy terminal to LisH (CTLH) E3 ligase, including the catalytic MAEA subunit, were among top screen hits. CTLH negatively regulates gluconeogenesis in yeast, but not in higher organisms. Instead, we identified that the CTLH substrates MKLN1 and ZMYND19, which highly accumulated upon MAEA knockout, associated with one another and with lysosomes to inhibit mTORC1. ZMYND19/MKLN1 bound Raptor and RagA/C, but rather than perturbing mTORC1 lysosomal recruitment, instead blocked a late stage of its activation, independently of the tuberous sclerosis complex. Thus, CTLH enables cells to rapidly tune mTORC1 activity at the lysosomal membrane via the ubiquitin/proteasome pathway.

Identifiers

PMID38746323
PMCPMC11092817

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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.