Vacuolar H+-ATPase-Ragulator-AXIN-LKB1-AMPK complex (v-ATPase-Ragulator-AXIN-LKB1-AMPK)

The Vacuolar H+-ATPase-Ragulator-AXIN-LKB1-AMPK complex is a multi-protein assembly on the lysosomal membrane that serves as a critical sensor for cellular energy and nutrient status, specifically glucose levels (NIH, 2014). It consists of the vacuolar H+-ATPase (v-ATPase) proton pump, the Ragulator complex (LAMTOR subunits), the scaffolding protein Axin-1, the upstream kinase Liver Kinase B1 (LKB1), and the energy sensor AMP-activated protein kinase (AMPK) (ResearchGate, 2025). In response to glucose starvation, the v-ATPase-Ragulator complex undergoes a conformational change that facilitates the recruitment of AXIN and LKB1 to the lysosome (NIH, 2017). Once localized, LKB1 phosphorylates AMPK at the Thr172 residue, activating it to trigger catabolic pathways and restore energy homeostasis (NIH, 2020). This activation also leads to the inhibition of the anabolic mTORC1 pathway, providing a coordinated switch between cell growth and energy conservation (NIH, 2014). Dysregulation of this complex is linked to metabolic diseases like type 2 diabetes and various cancers, making it a significant target for drugs like metformin, which activates AMPK through this lysosomal pathway (NIH, 2025). Pharmacological modulation of the complex, such as through v-ATPase inhibitors like archazolid or activators like metformin, offers potential therapeutic avenues for metabolic disorders and oncology (NIH, 2019). However, the essential role of v-ATPase in maintaining lysosomal pH across all cell types presents a challenge for achieving therapeutic selectivity and avoiding systemic toxicity (NIH, 2020).

Other names

v-ATPase-Ragulator-AXIN/LKB1-AMPK complexLysosomal AMPK activation complexv-ATPase-Ragulator-AXIN/LKB1 axisAXIN-based AMPK-activating complex

The complex acts as a lysosomal sensor for glucose; under low glucose conditions, the v-ATPase-Ragulator complex recruits AXIN and LKB1 to the lysosomal surface, where LKB1 phosphorylates and activates AMPK, while simultaneously inhibiting mTORC1 (NIH, 2014; NIH, 2025).