意大利那不勒斯费德里科二世大学Gennaro Napolitano研究组研制了TBK1/ULK1信号轴将溶酶体应激与TFEB激活偶联。相关论文于2026年9月30日发表在《自然》杂志上。

溶酶体对环境变化的适应对细胞和代谢稳态至关重要，并且需要mTORC1激酶的协调，mTORC1将营养和应激信号转化为不同的、底物特异性的输出。FLCN–FNIP复合物（FLCN:FNIP）通过选择性控制mTORC1抑制转录因子EB（TFEB）的能力，作为溶酶体功能的关键调控因子；TFEB是分解代谢程序的主调控因子，也是一种已知的癌基因。然而，FLCN:FNIP活性如何被调控仍不清楚。在此，研究人员鉴定出一条不依赖营养的溶酶体信号通路，该通路通过v-ATPase驱动的、经由TAX1BP1衔接蛋白将TBK1或ULK1（TBK1/ULK1）招募至溶酶体，从而调控FLCN。这使得TBK1/ULK1介导的FNIP1在S296位点磷酸化，导致FLCN抑制和TFEB核转位。在滤泡性淋巴瘤患者中发现的复发性ATP6V1B2 v-ATPase突变组成性激活该通路，导致TFEB过度激活和滤泡性淋巴瘤增殖。该工作揭示了一条对溶酶体适应和肿瘤发生至关重要的溶酶体信号通路。

附：英文原文

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

Author: Esposito, Alessandra, Bayramoglu, Ibrahim, Varriale, Chiara, Cavaliere, Maria Pia, Brunetti, Maria Elsa, Agostinis, Rossella, Jansen, Rachel M., Tudorica, Dan A., Duan, Yongjia, Spacci, Martina, Calcagn, Alessia, Strobl, Carolin D., Passerini, Verena, Andreone, Fabrizio, Monfregola, Jlenia, Richter, Julia, Sacco, Francesca, Klapper, Wolfram, Weigert, Oliver, Ballabio, Andrea, Zoncu, Roberto, Hurley, James H., Dengjel, Joern, Napolitano, Gennaro

Issue&Volume: 2026-09-30

Abstract: 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.

DOI: 10.1038/s41586-026-11093-3

Source: https://www.nature.com/articles/s41586-026-11093-3