التفاصيل البيبلوغرافية
| العنوان: |
Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterollowering compounds. |
| المؤلفون: |
Bao-cun Zhang, Laursen, Marlene F., Lili Hu, Hazrati, Hossein, Narita, Ryo, Jensen, Lea S., Hansen, Aida S., Jinrong Huang, Yan Zhang, Xiangning Ding, Muyesier, Maimaitili, Nilsson, Emil, Banasik, Agnieszka, Zeiler, Christina, Mogensen, Trine H., Etzerodt, Anders, Agger, Ralf, Johannsen, Mogens, Kofod-Olsen, Emil, Paludan, Søren R. |
| المصدر: |
Nature Communications; 3/29/2024, Vol. 15 Issue 1, p1-17, 17p, 5 Graphs |
| مستخلص: |
The cGAS-STING pathway plays a crucial role in anti-tumoral responses by activating inflammation and reprogramming the tumour microenvironment. Upon activation, STING traffics from the endoplasmic reticulum (ER) to Golgi, allowing signalling complex assembly and induction of interferon and inflammatory cytokines. Here we report that cGAMP stimulation leads to a transient decline in ER cholesterol levels, mediated by Sterol O-Acyltransferase 1-dependent cholesterol esterification. This facilitates ER membrane curvature and STING trafficking to Golgi. Notably, we identify two cholesterol-binding motifs in STING and confirm their contribution to ER-retention of STING. Consequently, depletion of intracellular cholesterol levels enhances STING pathway activation upon cGAMP stimulation. In a preclinical tumour model, intratumorally administered cholesterol depletion therapy potentiated STINGdependent anti-tumoral responses, which, in combination with anti-PD-1 antibodies, promoted tumour remission. Collectively, we demonstrate that ER cholesterol sets a threshold for STING signalling through cholesterol-binding motifs in STING and we propose that this could be exploited for cancer immunotherapy. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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