Presenilin enhancer 2 (PEN2) (PEN2)

Presenilin enhancer 2 (PEN2) is a small transmembrane protein traditionally recognized as an essential subunit of the gamma-secretase complex, where it facilitates the endoproteolysis of presenilin and the subsequent cleavage of substrates like amyloid precursor protein (APP) and Notch (UniProt P0C0L5). Recent research has identified a novel, gamma-secretase-independent role for PEN2 as the primary lysosomal receptor for the anti-diabetic drug metformin (Lin et al., Nature 2022). In this capacity, PEN2 forms a complex at the lysosomal membrane with the v-ATPase subunit ATP6AP1. Upon metformin binding, this PEN2-lysosomal complex initiates a signaling cascade that activates AMPK, a master regulator of metabolism, thereby mediating the drug's glucose-lowering and potential pro-longevity effects. This dual functionality makes PEN2 a critical target in both neurodegenerative research and metabolic medicine.

Other names

PSENENPresenilin enhancer protein 2Gamma-secretase subunit PEN-2PEN-2

Metformin binds directly to PEN2, which then interacts with the vacuolar ATPase (v-ATPase) subunit ATP6AP1 on the lysosomal membrane. This interaction inhibits v-ATPase activity and triggers the recruitment of the AXIN-LKB1 complex to the lysosome, leading to the activation of AMPK (adenosine monophosphate-activated protein kinase) independently of cellular energy status (Lin et al., Nature 2022).