Presenilin enhancer 2 (PEN-2)

Presenilin enhancer 2 (PEN-2) is a multi-functional protein that serves as a critical subunit of the gamma-secretase complex and a newly identified lysosomal glucose sensor. In its role within the gamma-secretase complex, it is essential for the intramembrane proteolysis of substrates such as Amyloid Precursor Protein (APP) and Notch (UniProt Q9NZ42). Recent research has demonstrated that PEN-2 also functions independently of its proteolytic role to sense low glucose levels on the lysosomal membrane. When glucose is scarce, PEN-2 binds to the ATP6V1A subunit of the vacuolar ATPase (v-ATPase), which triggers the assembly of a signaling complex including AXIN and LKB1 to activate AMP-activated protein kinase (AMPK) (Ma et al., 2022, Nature). This PEN-2-mediated lysosomal pathway is a primary mechanism through which the anti-diabetic drug metformin exerts its glucose-lowering effects at therapeutic concentrations. Consequently, the PEN-2-lysosomal complex represents a significant therapeutic target for metabolic disorders, obesity, and age-related diseases, although drug development must carefully navigate the potential for off-target effects on Notch signaling.

Other names

PSENENPresenilin enhancer protein 2PEN2Gamma-secretase subunit PEN-2

PEN-2 acts as a lysosomal glucose sensor; under low glucose conditions, it binds to the v-ATPase subunit ATP6V1A, facilitating the recruitment of the AXIN-LKB1 complex to the lysosome to phosphorylate and activate AMPK (Ma et al., 2022, Nature).