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The CTLH Ubiquitin Ligase Substrates ZMYND19 and MKLN1 Negatively Regulate mTORC1 at the Lysosomal Membrane
Open accessPreprint — published as 10.1038/s41467-025-65760-6 · Paper page
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.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., & Sabatini, D. M. (2013) · Science · doi:10.1126/science.1232044 · Cited by 1,080
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Metadata
- Authors
- Wang, Y., Guo, R., Piedras, B. I., Tang, H.-Y., Asara, J. M., Tempera, I., Lieberman, P. M., & Gewurz, B. E.
- Affiliations
- Broad Institute (US)
- The Wistar Institute (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Gewurz, Benjamin E.
- ORCID
- Venue
- Nature Communications
- Published
- 2024-04-24
- Volume
- 16
- Issue
- 1
- Pages
- 10731-10731
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC12663577
- OpenAlex
- W4416794512
- Cited by
- 7
- References
- 2
- Citations by year
- 2026: 4 · 2025: 3
- FWCI
- 2.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health and Human Services (P01CA269043, R00 DE031016)
- American Cancer Society (PF-24-1250090-01-IBCD, PF-24-1194768-01-TBE, PF-24-1308318-01-TBE, PF-23-1144614-01-IBCD)
- Burroughs Wellcome Fund
- Lymphoma Research Foundation
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (R01AI164709)
- National Institutes of Health
- National Cancer Institute (R50CA221838, P01CA120964, P01CA269043, P30CA010815)
- National Institute of Allergy and Infectious Diseases (R01AI164709)
- National Institute of Dental and Craniofacial Research (R00DE031016, R01DE033907)
- Division of Cancer Epidemiology and Genetics, National Cancer Institute (P01CA269043)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mTORC1, lysosomal membrane, PI3K/mTOR signaling, alpelisib, ubiquitin-proteasome system, Rheb, ribosomal protein S6, 4E-BP1, CRISPR-Cas9 screen, gluconeogenesis
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