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A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation
Nature
(2026) Cite this article
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 outputs1,2. 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 oncogene3. Yet how FLCN:FNIP activity is regulated has remained unclear. Here we identify a nutrient-independent lysosomal signalling pathway that regulates FLCN through v-ATPase-driven recruitment of TBK1 or ULK1 (TBK1/ULK1) to lysosomes, via the TAX1BP1 adaptor. This enables TBK1/ULK1-mediated FNIP1 phosphorylation at S296, resulting in inhibition of FLCN and nuclear translocation of TFEB. Recurrent ATP6V1B2 v-ATPase mutations, found in patients with follicular lymphoma, constitutively activate this pathway, leading to hyperactivation of TFEB and follicular lymphoma proliferation. Our work uncovers a lysosomal signalling pathway that is critical for lysosomal adaptation and tumorigenesis.
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Proteomic data have been deposited at the ProteomeXchange Consortium through the PRIDE partner repository with dataset identifiers PXD069600 (Fig. 2) and PXD063015 (Fig. 4). For gel source data, see Supplementary Fig. 3. Data are available from the corresponding author on reasonable request. Source data are provided with this paper.
Napolitano, G., Di Malta, C. & Ballabio, A. Non-canonical mTORC1 signaling at the lysosome. Trends Cell Biol. 32, 920–931 (2022).
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