PD-L1 degradation is regulated by electrostatic membrane association of its cytoplasmic domain

Maorong Wen (), Yunlei Cao, Bin Wu, Taoran Xiao, Ruiyu Cao, Qian Wang, Xiwei Liu, Hongjuan Xue, Yang Yu, Jialing Lin, Chenqi Xu, Jie Xu and Bo OuYang ()
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Maorong Wen: Chinese Academy of Sciences
Yunlei Cao: Chinese Academy of Sciences
Bin Wu: Chinese Academy of Sciences
Taoran Xiao: Chinese Academy of Sciences
Ruiyu Cao: Chinese Academy of Sciences
Qian Wang: Chinese Academy of Sciences
Xiwei Liu: Chinese Academy of Sciences
Hongjuan Xue: Chinese Academy of Sciences
Yang Yu: Chinese Academy of Sciences
Jialing Lin: University of Oklahoma Health Sciences Center
Chenqi Xu: Chinese Academy of Sciences
Jie Xu: Fudan University
Bo OuYang: Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25416-7

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