Presenilin enhancer protein 2–lysosomal vacuolar-type H+-ATPase complex (PEN-2–v-ATPase)

The Presenilin enhancer protein 2–lysosomal vacuolar-type H+-ATPase complex is a multi-protein assembly that serves as a pivotal hub for cellular energy sensing and lysosomal maintenance [1]. Presenilin enhancer 2 (PEN-2), traditionally recognized as a core subunit of the gamma-secretase complex, has been recently identified as a direct sensor for glucose on the lysosomal membrane [2]. Under conditions of glucose starvation, the absence of glucose binding allows PEN-2 to interact with the ATP6V1A subunit of the vacuolar-type H+-ATPase (v-ATPase), which triggers the recruitment of the AXIN-LKB1 complex to activate AMP-activated protein kinase (AMPK) [1, 4]. Beyond its role in metabolic signaling, this complex is essential for maintaining the acidic environment of the lysosome, which is required for the degradation of cellular waste via autophagy [2]. Impairment of the PEN-2–v-ATPase interaction is linked to the pathogenesis of Alzheimer's disease, as it leads to lysosomal alkalization and the accumulation of amyloid-beta and tau aggregates [3]. Consequently, this complex represents a novel therapeutic target for both metabolic diseases and neurodegeneration, offering a mechanism to modulate energy balance and enhance proteostatic clearance [1, 4].

Other names

PEN2-v-ATPase complexPSENEN-v-ATPase complexPresenilin enhancer 2-vacuolar H+-ATPase complexPEN-2–v-ATPase–AMPK complex

Glucose-dependent recruitment of the AXIN-LKB1 complex to the v-ATPase for AMPK activation and regulation of lysosomal pH.