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Publication Abstract from PubMed

The cytoplasmic domain of PD-L1 (PD-L1-CD) regulates PD-L1 degradation and stability through various mechanism, making it an attractive target for blocking PD-L1-related cancer signaling. Here, by using NMR and biochemical techniques we find that the membrane association of PD-L1-CD is mediated by electrostatic interactions between acidic phospholipids and basic residues in the N-terminal region. The absence of the acidic phospholipids and replacement of the basic residues with acidic residues abolish the membrane association. Moreover, the basic-to-acidic mutations also decrease the cellular abundance of PD-L1, implicating that the electrostatic interaction with the plasma membrane mediates the cellular levels of PD-L1. Interestingly, distinct from its reported function as an activator of AMPK in tumor cells, the type 2 diabetes drug metformin enhances the membrane dissociation of PD-L1-CD by disrupting the electrostatic interaction, thereby decreasing the cellular abundance of PD-L1. Collectively, our study reveals an unusual regulatory mechanism that controls the PD-L1 level in tumor cells, suggesting an alternative strategy to improve the efficacy of PD-L1-related immunotherapies.

PD-L1 degradation is regulated by electrostatic membrane association of its cytoplasmic domain.,Wen M, Cao Y, Wu B, Xiao T, Cao R, Wang Q, Liu X, Xue H, Yu Y, Lin J, Xu C, Xu J, OuYang B Nat Commun. 2021 Aug 24;12(1):5106. doi: 10.1038/s41467-021-25416-7. PMID:34429434^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.