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.
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PD-L1 的同二聚化胞质结构域调节其在活细胞中的复杂糖基化
DOI：
10.1038/s42003-022-03845-4
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发表时间：
2022-08-30
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
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作者：
膜锚定的PD-L1是否在活细胞中同源二聚化是有争议的。同二聚体的生物学意义有待迅速探索。然而，膜锚定全长PD-L1同源二聚体的表征具有挑战性，需要非常规方法。通过使用基因掺入的交联剂，我们表明全长PD-L1在活细胞中形成同源二聚体和四聚体。重要的是，PD-L1的同源二聚化胞内结构域在其复杂的糖基化中发挥关键作用。进一步的分析确定了PD-L1细胞内结构域中的三个关键精氨酸残基作为调节单位。在PD-L1/PD-L1- 3 RE同二聚体中，突变导致野生型PD-L1的膜丰度减少和高尔基体增加。值得注意的是，PD-1与癌细胞上异常糖基化的PD-L1的结合减弱，随后T细胞诱导的毒性增加。总的来说，我们的研究表明PD-L1确实在细胞中形成同源二聚体，并且同源二聚体在PD-L1复合物糖基化和T细胞介导的毒性中起重要作用。膜锚定的PD-L1在细胞中同源二聚化。PD-L1的N-糖基化调节其同源二聚化。PD-L1同源二聚体的形成进一步调节其聚糖加工、定位于质膜以及与PD-1的结合。
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. Membrane-anchored PD-L1 homodimerizes in cells. N-glycosylation of PD-L1 regulates its homodimerization. The formation of PD-L1 homodimers further regulates their glycan processing, localization to the plasma membrane, and binding to PD-1.
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影响因子：
7.3
作者：
Guzik, Katarzyna;Zak, Krzysztof M.;Holak, Tad A.
通讯作者：
Holak, Tad A.
影响因子：
8.8
作者：
Gato-Canas, Maria;Zuazo, Miren;Escors, David
通讯作者：
Escors, David
影响因子：
16.6
作者：
Ahmed Z;Timsah Z;Suen KM;Cook NP;Lee GR 4th;Lin CC;Gagea M;Marti AA;Ladbury JE
通讯作者：
Ladbury JE
影响因子：
14.8
作者：
通讯作者：
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PD-1检查点途径的分子和生化方面。
DOI：
10.1056/nejmra1514296
发表时间：
2016-11-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
Boussiotis VA
通讯作者：
Boussiotis VA