Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity
By Chia‐Wei Li, Seung-Oe Lim, W. Xia, Heng-Huan Lee, Li-Chuan Chan, Chu-Wei Kuo, K. Khoo, Shih-Shin Chang, Jong-Ho Cha, Taewan Kim and 14 more. Nature Communications, 2016
993 citations recorded by the source corpus.
Extracellular interaction between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) leads to tumour-associated immune escape. Here we show that the immunosuppression activity of PD-L1 is stringently modulated by ubiquitination and N-glycosylation. We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP. In-depth analysis of PD-L1 N192, N200 and N219 glycosylation suggests that glycosylation antagonizes GSK3β binding. In this regard, only non-glycosylated PD-L1 forms a complex with GSK3β and β-TrCP. We also demonstrate that epidermal growth factor (EGF) stabilizes PD-L1 via GSK3β inactivation in basal-like breast cancer. Inhibition of EGF signalling by gefitinib destabilizes PD-L1, enhances antitumour T-cell immunity and therapeutic efficacy of PD-1 blockade in syngeneic mouse models. Together, our results link ubiquitination and glycosylation pathways to the stringent regulation of PD-L1, which could lead to potential therapeutic strategies to enhance cancer immune therapy efficacy. Programmed Death ligand-1 (PD-L1) protein mediates immune suppression in cancer. Here, the authors show that in breast cancer, PD-L1 expression can be up regulated post-translationally by glycosylation, which in turn acts through inhibiting GSK3β-mediated PD-L1 degradation.
Subfields: Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/48d3a6f4b5cc1cebb5b56dd831726cff5e9e917d
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Citations in the corpus
- Deubiquitination and Stabilization of PD-L1 by CSN5 (2016, methodology): “4T1 or EMT6 cells (5 3 104 cells) in 50 mL of medium mixed with 50 mL of Matrigel (BD) were injected into the mammary fat fad (Li et al., 2016).”
- Cyclin D-CDK4 kinase destabilizes PD-L1 via Cul3SPOP to control cancer immune surveillance (2017, positive): “Although it has been reported that PD-L1 expression can be regulated at both transcriptional 9,10 and post-translational levels 11,12 , it remains unclear whether PD-L1 stability is regulated under physiological conditions such as during cell cycle progression.”
- PD-L1-Mediated Gasdermin C Expression Switches Apoptosis to Pyroptosis in Cancer Cells and Facilitates Tumor Necrosis (2020, background): “The N-terminal domain (1-365) of GSDMC is sufficient to induce pyroptosis (a) 3-D structural modeling of GSDMC.”
- Mechanisms controlling PD-L1 expression in cancer (2019, background): “, 2019), tyrosine kinase inhibitor, and resveratrol (Li et al., 2016) all have been reported to directly or indirectly regulate GSK3β activity to alter PD-L1 and β-TrCP interaction.”
- Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory (2019, background): “To determine whether exosomal PD-L1 directly arises from the ER or early Golgi, we took advantage of the fact that PD-L1 is glycosylated (Li et al., 2016).”
- Metformin promotes antitumor immunity via endoplasmic reticulum-associated degradation of PD-L1 (2018, positive): “Immunohistochemical staining was performed as previously described (Li et al., 2016) using PD-L1 (205921, 1:150; Abcam) and AMPKa Thr172-p (2535S, 1:30; Cell Signaling Technology) antibodies.”
- PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression (2017, result): “The finding that PARPi inactivates GSK3α/β is also in line with our recent report demonstrating inactivation of GSK3β (p-Ser9) stabilizes PD-L1 [27].”