Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity.
Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity.
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程序性死亡配体-1的糖基化和稳定化抑制t细胞活性。
DOI：
10.1038/ncomms12632
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发表时间：
2016-08-30
影响因子：
16.6
通讯作者：
Hung, Mien-Chie
中科院分区：
文献类型：
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作者：
Li, Chia-Wei;Lim, Seung-Oe;Xia, Weiya;Lee, Heng-Huan;Chan, Li-Chuan;Kuo, Chu-Wei;Khoo, Kay-Hooi;Chang, Shih-Shin;Cha, Jong-Ho;Kim, Taewan;Hsu, Jennifer L.;Wu, Yun;Hsu, Jung-Mao;Yamaguchi, Hirohito;Ding, Qingqing;Wang, Yan;Yao, Jun;Lee, Cheng-Chung;Wu, Hsing-Ju;Sahin, Aysegul A.;Allison, James P.;Yu, Dihua;Hortobagyi, Gabriel N.;Hung, Mien-Chie
程序性死亡配体-1（PD-L1）和程序性细胞死亡蛋白-1（PD-1）之间的细胞外相互作用导致肿瘤相关免疫逃逸。在这里，我们表明PD-L1的免疫抑制活性受到泛素化和N-糖基化的严格调节。我们发现，糖原合成酶激酶3β（GSK 3 β）与PD-L1相互作用，并通过β-TrCP诱导PD-L1的磷酸化依赖性蛋白酶体降解。PD-L1 N192、N200和N219糖基化的深入分析表明，糖基化拮抗GSK 3 β结合。在这方面，只有非糖基化的PD-L1与GSK 3 β和β-TrCP形成复合物。我们还证明了表皮生长因子（EGF）通过GSK 3 β失活稳定基底样乳腺癌中的PD-L1。吉非替尼抑制EGF信号传导使PD-L1不稳定，增强抗肿瘤T细胞免疫力和同基因小鼠模型中PD-1阻断的治疗功效。总之，我们的研究结果将泛素化和糖基化途径与PD-L1的严格调控联系起来，这可能导致潜在的治疗策略，以提高癌症免疫治疗的疗效。 程序性死亡配体-1（PD-L1）蛋白介导癌症中的免疫抑制。在这里，作者表明，在乳腺癌中，PD-L1表达可以通过糖基化在术后上调，糖基化反过来又通过抑制GSK 3 β介导的PD-L1降解起作用。
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.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
影响因子：
6.8
作者：
Schwarz, Flavio;Aebi, Markus
通讯作者：
Aebi, Markus
影响因子：
5.3
作者：
Ding, Qingqing;He, Xianghuo;Hung, Mien-Chie
通讯作者：
Hung, Mien-Chie
影响因子：
--
作者：
Hudak JE;Bertozzi CR
通讯作者：
Bertozzi CR