The tumor suppressor CYLD acts as a deubiquitinase for mTOR to constrain its activity

Fernandes SA, Pan J, Terziyska DS, Koyuncu S, Ding X, Németh IB, Wilhelm S, Nüchel J, Al-Gburi S, Gonidas C, Pasparakis M, …, Demetriades C · 2025 · bioRxiv · Atlas ID FER2025

What this study shows

An RNAi screen identified the tumor suppressor CYLD as a deubiquitinase that binds mTOR and removes non-degradative K63-linked ubiquitin chains from several of its residues, restraining both mTORC1 and mTORC2. Cells lacking CYLD show hyperactive mTORC1/2, higher protein synthesis, larger cell size and resistance to serum-starvation-induced cell death. In C. elegans, knocking down cyld-1 fully abolishes the extended lifespan of low-TORC1-activity mutants, and skin biopsies from CYLD cutaneous syndrome patients show mTORC1 hyperactivation. Preprint, not peer-reviewed.

Abstract

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Proper control of mTOR (mechanistic/mammalian target of rapamycin) signaling is relevant for health, disease and ageing. Information from intra- and extra-cellular signaling cues is transmitted to mTOR through an intricate signaling network that impinges on the Rag and Rheb GTPases to regulate its localization and activity. Interestingly, although mTOR is a heavily ubiquitinated protein, the role of this post-translational modification (PTM) in regulating its activation status remains poorly understood.

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At a glance

Evidence type	PP Preprint, not peer-reviewed This is a preprint, not yet peer-reviewed -- treat its findings as provisional until formal publication. Preprints carry their own marker because peer-review status is a different question from which system was studied.
Study type	Preprint
Model system	Human cell lines (RNAi screen, CYLD loss of function); C. elegans cyld-1 knockdown in low-TORC1 lifespan mutants; skin biopsies from CYLD cutaneous syndrome patients
Journal	bioRxiv
Year	2025
Peer reviewed	No
Record last updated	2026-10-01
Source	DOI 10.1101/2025.09.01.673523 · PMID 40950055 · Free full text (PMC12424753)

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	CYLD knockdown/loss of function; cyld-1 RNAi in C. elegans
Target	mTOR K63-linked ubiquitination; mTORC1 and mTORC2 activity
Model	Human cells; C. elegans; human skin biopsies
Effect	CYLD loss raised mTORC1/2 activity, protein synthesis and cell size; cyld-1 knockdown reversed lifespan extension of low-TORC1 worms

In the Atlas

Cite this paper

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Fernandes, S. A., Pan, J., Terziyska, D. S., Koyuncu, S., Ding, X., Németh, I. B., Wilhelm, S., Nüchel, J., Al-Gburi, S., Gonidas, C., Pasparakis, M., Mosialos, G., Széll, M., Teleman, A. A., Eming, S. A., Vilchez, D., & Demetriades, C. (2025). The tumor suppressor CYLD acts as a deubiquitinase for mTOR to constrain its activity. bioRxiv. https://doi.org/10.1101/2025.09.01.673523

@article{FER2025,
  author       = {Fernandes, S. A. and Pan, J. and Terziyska, D. S. and Koyuncu, S. and Ding, X. and Németh, I. B. and Wilhelm, S. and Nüchel, J. and Al-Gburi, S. and Gonidas, C. and Pasparakis, M. and Mosialos, G. and Széll, M. and Teleman, A. A. and Eming, S. A. and Vilchez, D. and Demetriades, C.},
  title        = {{The tumor suppressor CYLD acts as a deubiquitinase for mTOR to constrain its activity}},
  journal      = {bioRxiv},
  year         = {2025},
  doi          = {10.1101/2025.09.01.673523},
  note         = {PMID: 40950055},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record FER2025) [Data set]. https://mtor-atlas.org/study/FER2025/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_FER2025,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record FER2025},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/FER2025/},
  doi          = {10.5281/zenodo.22059963}
}

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