A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation.

Esposito A, Bayramoglu I, Varriale C, Cavaliere MP, Brunetti ME, Agostinis R, Jansen RM, Tudorica DA, Duan Y, Spacci M, Calcagnì A, …, Napolitano G · 2026 · Nature · Atlas ID ESP2026

What this study shows

Identifies a nutrient-independent lysosomal pathway in which v-ATPase recruits TBK1/ULK1 to phosphorylate FNIP1, inhibiting the FLCN:FNIP complex and releasing TFEB for nuclear translocation; recurrent ATP6V1B2 mutations found in follicular lymphoma patients constitutively hyperactivate this axis, driving TFEB-dependent tumor proliferation.

Abstract

ShowHide

Lysosomal adaptation to environmental changes is critical for cellular and metabolic homeostasis and requires coordination by the mTORC1 kinase, which conveys nutritional and stress signals into distinct, substrate-specific outputs. The FLCN-FNIP complex (FLCN:FNIP) serves as a crucial regulator of lysosomal function by selectively controlling the ability of mTORC1 to inhibit transcription factor EB (TFEB), a master regulator of catabolic programs and a known oncogene. Yet how FLCN:FNIP activity is regulated has remained unclear.

Read the full abstract on PubMed →

At a glance

Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Human cell lines; ATP6V1B2-mutant follicular lymphoma patient samples) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type	5 - Mechanistic / In Vitro
Model system	Human cell lines; ATP6V1B2-mutant follicular lymphoma patient samples
Journal	Nature
Year	2026
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1038/s41586-026-11093-3 · PMID 42816627

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	Genetic and pharmacological perturbation of v-ATPase, TBK1/ULK1, TAX1BP1 and FNIP1 (S296 phospho-mutants); lysosomal stress
Target	v-ATPase - TBK1/ULK1 - FNIP1 S296 - FLCN:FNIP - TFEB
Model	Human cell lines; follicular lymphoma patient samples
Effect	Lysosomal stress recruits TBK1/ULK1 to phosphorylate FNIP1, inhibiting FLCN and driving TFEB nuclear translocation; recurrent ATP6V1B2 mutations hyperactivate this axis and promote lymphoma cell proliferation.

In the Atlas

Links in the pathway map

Supports ULK1 inhibits FLCN / FNIP1/2

Cite this paper

ShowHide

Esposito, A., Bayramoglu, I., Varriale, C., Cavaliere, M. P., Brunetti, M. E., Agostinis, R., Jansen, R. M., Tudorica, D. A., Duan, Y., Spacci, M., Calcagnì, A., Strobl, C. D., Passerini, V., Andreone, F., Monfregola, J., Richter, J., Sacco, F., Klapper, W., Weigert, O., Ballabio, A., Zoncu, R., Hurley, J. H., Dengjel, J., & Napolitano, G. (2026). A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation. Nature. https://doi.org/10.1038/s41586-026-11093-3

@article{ESP2026,
  author       = {Esposito, A. and Bayramoglu, I. and Varriale, C. and Cavaliere, M. P. and Brunetti, M. E. and Agostinis, R. and Jansen, R. M. and Tudorica, D. A. and Duan, Y. and Spacci, M. and Calcagnì, A. and Strobl, C. D. and Passerini, V. and Andreone, F. and Monfregola, J. and Richter, J. and Sacco, F. and Klapper, W. and Weigert, O. and Ballabio, A. and Zoncu, R. and Hurley, J. H. and Dengjel, J. and Napolitano, G.},
  title        = {{A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation}},
  journal      = {Nature},
  year         = {2026},
  doi          = {10.1038/s41586-026-11093-3},
  note         = {PMID: 42816627},
}

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 ESP2026) [Data set]. https://mtor-atlas.org/study/ESP2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_ESP2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record ESP2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/ESP2026/},
  doi          = {10.5281/zenodo.22059963}
}

Was this page useful?