AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is the main sensor of energy stress, playing a part in adaptive responses to falling energy levels. AMPK is a heterotrimeric protein complex, comprised of a catalytic α subunit (PRKAA1,PRKAA2), a β subunit (PRKAB1, PRKAB2), and a γ subunits (PRKAG1, PRKAG2, PRKAG3). During energy deprivation, cellular levels of AMP are increased while ATP levels decline, leading to AMPK activation because of allosteric changes.. Activated AMPK phosphorylates PD-L1 (CD274) at S195 which leads to abnormal glycosylation due to improper mannose trimming, thus leading to endoplasmic reticulum (ER) accumulation of PD-L1 and activation of ER-associated protein degradation (ERAD) pathway for the degradation of abnormally glycosylated PD-L1. AMPK promotes not only ERAD-mediated but also lysosome-mediated degradation of PD-L1. Mechanistically, activated AMPK phosphorylates a specific serine residue (Ser283) on PD-L1, which disrupts its interaction with CMTM4 and consequently facilitates PD-L1 degradation via the lysosomal pathway.

Summary from Reactome (R-HSA-9931269), read 2026-09-23.