Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis

Ferniani M, Sambri I, Huynh T, Pennella R, Tufano G, Herz NJ, Rossi B, Iannaccone A, Trepiccione F, Calcagnì A, Ballabio A · 2026 · Cell Death and Differentiation · Atlas ID FER2026

What this study shows

Using kidney-specific mouse models that genetically uncouple mTORC1 activity from TFEB/TFE3 activity (Depdc5-KO, RagC-KO, and Flcn/RagC double-KO), the authors show mTORC1 hyperactivation -- not TFEB/TFE3 activation alone -- is the primary driver of kidney cystogenesis and tumorigenesis in Birt-Hogg-Dube and Tuberous Sclerosis Complex models. Constitutive TFEB/TFE3 activity further accelerates disease on top of mTORC1-driven pathology.

Abstract

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Birt-Hogg-Dubé (BHD) and Tuberous Sclerosis (TSC) are inherited cancer syndromes associated with kidney cystogenesis and tumorigenesis and caused by mutations of the folliculin (FLCN) and TSC1/2 genes, respectively. We and others previously showed that Transcription Factors EB (TFEB) and E3 (TFE3) are the main drivers of the kidney phenotypes observed in mouse models of these conditions. These transcription factors are also responsible for the feedback hyperactivation of the mechanistic Target of Rapamycin Complex 1 (mTORC1), a known tumorigenic factor.

Read the full abstract on PubMed →

At a glance

Evidence type	A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Kidney-specific conditional knockout mice: Depdc5-KO, RagC-KO, and Flcn/RagC double-KO (models of Birt-Hogg-Dube and Tuberous Sclerosis Complex)); the code names the system studied -- animal work can be rigorous and still not be human data.
Study type	4 - Animal Study
Model system	Kidney-specific conditional knockout mice: Depdc5-KO, RagC-KO, and Flcn/RagC double-KO (models of Birt-Hogg-Dube and Tuberous Sclerosis Complex)
Journal	Cell Death and Differentiation
Year	2026
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1038/s41418-026-01881-9 · PMID 42816660

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	Kidney-specific Depdc5, RagC and Flcn/RagC conditional knockouts
Target	mTORC1 vs TFEB/TFE3 in kidney cystogenesis
Model	Mouse (kidney)
Effect	mTORC1 hyperactivation is a key driver of kidney cysts and tumours; constitutive TFEB/TFE3 activity accelerates the pathology.

In the Atlas

Links in the pathway map

Supports mTORC1 activates Tumor growth

Cite this paper

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Ferniani, M., Sambri, I., Huynh, T., Pennella, R., Tufano, G., Herz, N. J., Rossi, B., Iannaccone, A., Trepiccione, F., Calcagnì, A., & Ballabio, A. (2026). Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis. Cell Death and Differentiation. https://doi.org/10.1038/s41418-026-01881-9

@article{FER2026,
  author       = {Ferniani, M. and Sambri, I. and Huynh, T. and Pennella, R. and Tufano, G. and Herz, N. J. and Rossi, B. and Iannaccone, A. and Trepiccione, F. and Calcagnì, A. and Ballabio, A.},
  title        = {{Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis}},
  journal      = {Cell Death and Differentiation},
  year         = {2026},
  doi          = {10.1038/s41418-026-01881-9},
  note         = {PMID: 42816660},
}

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 FER2026) [Data set]. https://mtor-atlas.org/study/FER2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_FER2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record FER2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/FER2026/},
  doi          = {10.5281/zenodo.22059963}
}

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