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

Lysosomal stress activates a TBK1/ULK1 pathway that inhibits FLCN and promotes TFEB-driven tumor growth, with mutations in v-ATPase amplifying this effect.

• Why it matters: Understanding how lysosomal signals regulate cellular adaptation and tumor progression is vital, especially since dysregulation of TFEB and lysosomal pathways is linked to cancer.
• What they did: The study identified a lysosomal signaling pathway involving v-ATPase, TAX1BP1, TBK1/ULK1, and FLCN, with phosphorylation of FNIP1 at S296 leading to TFEB activation, using biochemical and genetic approaches.
• The result: This pathway's activation enhances lysosomal function and tumor proliferation, revealing potential targets for therapeutic intervention in cancers with v-ATPase mutations like follicular lymphoma.