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

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. (Dai et al., 2021). 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 (Cha et al., 2018). 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 (Dai et al., 2021).