The phosphorylation by activated-AMPK induces ERAD of PD-L1 through abnormal glycosylation

초록

Programmed death ligand-1 (PD-L1) is a major immune checkpoint molecule that enables cancer immune evasion in various cancer types and therefore, the PD-L1/PD-1 axis has been a major target for current cancer immune checkpoint blockade (ICB). However, the regulatory mechanisms of PD-L1 expression are largely undefined. Here, we demonstrate that AMP-activated protein kinase (AMPK) phosphorylates Serine 195 of PD-L1 and which induces the ER-associated degradation (ERAD) of PD-L1 via abnormal glycosylation. Further, we identified HRD1 as an ERAD E3 ligase of PD-L1. Ser195-p recruits HRD1 into PD-L1-ERAD complex and finally induce proteasomal degradation of PD-L1 through poly-ubiquitination. This study broadens our understanding of the regulation of PD-L1 expression and which has the potential to improve the efficacy of ICB targeting PD-L1/PD-1 and overcome resistance to the ICB.