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

  • Nat Commun. 2021 Aug 24;12(1):5106. doi: 10.1038/s41467-021-25416-7.
Maorong Wen   #  1 ,  Yunlei Cao   #  2  3 ,  Bin Wu   #  4 ,  Taoran Xiao  2  3 ,  Ruiyu Cao  2  3 ,  Qian Wang  2  3 ,  Xiwei Liu  2  3 ,  Hongjuan Xue  4 ,  Yang Yu  4 ,  Jialing Lin  5  6 ,  Chenqi Xu  2  3 ,  Jie Xu  7 ,  Bo OuYang  8  9
Affiliations
  • 1. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 2. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
  • 3. University of Chinese Academy of Sciences, Beijing, China.
  • 4. National Facility for Protein Science in Shanghai, ZhangJiang lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China.
  • 5. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
  • 6. Stephenson Cancer Center, Oklahoma City, OK, USA.
  • 7. Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 8. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 9. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 34429434 DOI: 10.1038/s41467-021-25416-7
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.

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