Presenilin enhancer 2–ATP6AP1–vacuolar-type H+-ATPase complex (PEN2–ATP6AP1–v-ATPase)

The Presenilin enhancer 2 (PEN-2)–ATP6AP1–vacuolar-type H+-ATPase (v-ATPase) complex is a multi-protein assembly on the lysosomal membrane that serves as a critical junction between cellular energy status and metabolic signaling (Lin et al., 2022, Nature). PEN-2, traditionally recognized as an essential subunit of the gamma-secretase complex involved in the proteolytic processing of the amyloid precursor protein (APP) (UniProt Q9NZ42), has been recently identified to function as a direct sensor for cytosolic glucose. When glucose levels are low, PEN-2 binds to the ATP6AP1 (Ac45) subunit of the v-ATPase, facilitating the recruitment of the AXIN-LKB1 complex to the lysosome to activate AMP-activated protein kinase (AMPK) (PubMed 35322231). This interaction effectively couples the cell's nutrient-sensing machinery with the v-ATPase proton pump, which is responsible for maintaining the acidic environment necessary for lysosomal degradation. Because of its dual role in both metabolic regulation and neurodegeneration-linked proteolysis, this complex is a high-interest therapeutic target for conditions such as type 2 diabetes, obesity, and Alzheimer's disease. However, pharmacological modulation of this complex poses significant challenges, as disrupting PEN-2's function could interfere with Notch signaling or lead to lysosomal dysfunction (Lin et al., 2022, Nature).

Other names

PEN2-ATP6AP1 complexPEN-2-v-ATPase complexPresenilin enhancer 2-ATP6AP1-v-ATPase lysosomal complexPSENEN-ATP6AP1-v-ATPase complex

Facilitates lysosomal AMPK activation in response to low glucose levels by bridging the v-ATPase complex and AMPK (Lin et al., 2022, Nature).