The CTLH ubiquitin ligase substrates ZMYND19 and MKLN1 negatively regulate mTORC1 at the lysosomal membrane

Yin Wang, Yifei Liao, Yizhe Sun, Bidisha Mitra, Rui Guo, Brenda Iturbide Piedras, Shaowen White, Hsin-Yao Tang, John M. Asara, Italo Tempera, Paul M. Lieberman and Benjamin E. Gewurz ()
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Yin Wang: Brigham and Women’s Hospital, Division of Infectious Diseases, Department of Medicine
Yifei Liao: Brigham and Women’s Hospital, Division of Infectious Diseases, Department of Medicine
Yizhe Sun: Brigham and Women’s Hospital, Division of Infectious Diseases, Department of Medicine
Bidisha Mitra: Brigham and Women’s Hospital, Division of Infectious Diseases, Department of Medicine
Rui Guo: Brigham and Women’s Hospital, Division of Infectious Diseases, Department of Medicine
Brenda Iturbide Piedras: Brigham and Women’s Hospital, Division of Infectious Diseases, Department of Medicine
Shaowen White: Brigham and Women’s Hospital, Division of Infectious Diseases, Department of Medicine
Hsin-Yao Tang: The Wistar Institute
John M. Asara: Harvard Medical School, Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine
Italo Tempera: The Wistar Institute
Paul M. Lieberman: The Wistar Institute
Benjamin E. Gewurz: Brigham and Women’s Hospital, Division of Infectious Diseases, Department of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: 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 perform 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, are among top screen hits. CTLH negatively regulates gluconeogenesis in yeast, but not in higher organisms. The CTLH substrates MKLN1 and ZMYND19, which highly accumulated upon MAEA knockout, associate with one another and with lysosome outer membranes to inhibit mTORC1. Rather than perturbing mTORC1 lysosomal recruitment, ZMYND19 and MKLN1 block the interaction between mTORC1 and Rheb and also with mTORC1 substrates S6 and 4E-BP1. Thus, CTLH enables cells to rapidly tune mTORC1 activity at the lysosomal membrane via the ubiquitin/proteasome pathway.

Date: 2025
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DOI: 10.1038/s41467-025-65760-6

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