1. Academic Validation
  2. Homodimerized cytoplasmic domain of PD-L1 regulates its complex glycosylation in living cells

Homodimerized cytoplasmic domain of PD-L1 regulates its complex glycosylation in living cells

  • Commun Biol. 2022 Aug 30;5(1):887. doi: 10.1038/s42003-022-03845-4.
Li Zhou  # 1 Fangni Chai  # 1 Yong He  # 1 Zhihui Zhou 1 Shupan Guo 1 Pan Li 1 Qi Sun 1 Xueyin Zu 1 Xin Liu 1 Qin Huang 1 Yanping Zhong 1 Aolan Zhou 1 Xueyun Wang 1 Haiyan Ren 2 3
Affiliations

Affiliations

  • 1 Division of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, 610041, Chengdu, China.
  • 2 Division of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, 610041, Chengdu, China. hyren@scu.edu.cn.
  • 3 Collaborative Innovation Center of Biotherapy, 610041, Chengdu, China. hyren@scu.edu.cn.
  • # Contributed equally.
Abstract

Whether membrane-anchored PD-L1 homodimerizes in living cells is controversial. The biological significance of the homodimer waits to be expeditiously explored. However, characterization of the membrane-anchored full-length PD-L1 homodimer is challenging, and unconventional approaches are needed. By using genetically incorporated crosslinkers, we showed that full length PD-L1 forms homodimers and tetramers in living cells. Importantly, the homodimerized intracellular domains of PD-L1 play critical roles in its complex glycosylation. Further analysis identified three key arginine residues in the intracellular domain of PD-L1 as the regulating unit. In the PD-L1/PD-L1-3RE homodimer, mutations result in a decrease in the membrane abundance and an increase in the Golgi of wild-type PD-L1. Notably, PD-1 binding to abnormally glycosylated PD-L1 on Cancer cells was attenuated, and subsequent T-cell induced toxicity increased. Collectively, our study demonstrated that PD-L1 indeed forms homodimers in cells, and the homodimers play important roles in PD-L1 complex glycosylation and T-cell mediated toxicity.

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