Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds
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Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds. / Zhang, Bao Cun; Laursen, Marlene F.; Hu, Lili; Hazrati, Hossein; Narita, Ryo; Jensen, Lea S.; Hansen, Aida S.; Huang, Jinrong; Zhang, Yan; Ding, Xiangning; Muyesier, Maimaitili; Nilsson, Emil; Banasik, Agnieszka; Zeiler, Christina; Mogensen, Trine H.; Etzerodt, Anders; Agger, Ralf; Johannsen, Mogens; Kofod-Olsen, Emil; Paludan, Søren R.; Jakobsen, Martin R.
In: Nature Communications, Vol. 15, No. 1, 2760, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds
AU - Zhang, Bao Cun
AU - Laursen, Marlene F.
AU - Hu, Lili
AU - Hazrati, Hossein
AU - Narita, Ryo
AU - Jensen, Lea S.
AU - Hansen, Aida S.
AU - Huang, Jinrong
AU - Zhang, Yan
AU - Ding, Xiangning
AU - Muyesier, Maimaitili
AU - Nilsson, Emil
AU - Banasik, Agnieszka
AU - Zeiler, Christina
AU - Mogensen, Trine H.
AU - Etzerodt, Anders
AU - Agger, Ralf
AU - Johannsen, Mogens
AU - Kofod-Olsen, Emil
AU - Paludan, Søren R.
AU - Jakobsen, Martin R.
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - 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 STING-dependent 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.
AB - 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 STING-dependent 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.
U2 - 10.1038/s41467-024-47046-5
DO - 10.1038/s41467-024-47046-5
M3 - Journal article
C2 - 38553448
AN - SCOPUS:85189018234
VL - 15
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2760
ER -
ID: 387837059