Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds

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Standard

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.

I: Nature Communications, Bind 15, Nr. 1, 2760, 2024.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Zhang, BC, Laursen, MF, Hu, L, Hazrati, H, Narita, R, Jensen, LS, Hansen, AS, Huang, J, Zhang, Y, Ding, X, Muyesier, M, Nilsson, E, Banasik, A, Zeiler, C, Mogensen, TH, Etzerodt, A, Agger, R, Johannsen, M, Kofod-Olsen, E, Paludan, SR & Jakobsen, MR 2024, 'Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds', Nature Communications, bind 15, nr. 1, 2760. https://doi.org/10.1038/s41467-024-47046-5

APA

Zhang, B. C., Laursen, M. F., Hu, L., Hazrati, H., Narita, R., Jensen, L. S., Hansen, A. S., Huang, J., Zhang, Y., Ding, X., Muyesier, M., Nilsson, E., Banasik, A., Zeiler, C., Mogensen, T. H., Etzerodt, A., Agger, R., Johannsen, M., Kofod-Olsen, E., ... Jakobsen, M. R. (2024). Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds. Nature Communications, 15(1), [2760]. https://doi.org/10.1038/s41467-024-47046-5

Vancouver

Zhang BC, Laursen MF, Hu L, Hazrati H, Narita R, Jensen LS o.a. Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds. Nature Communications. 2024;15(1). 2760. https://doi.org/10.1038/s41467-024-47046-5

Author

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. / Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds. I: Nature Communications. 2024 ; Bind 15, Nr. 1.

Bibtex

@article{eac9a8aee04a45b89e3b7980708fec61,
title = "Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds",
abstract = "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.",
author = "Zhang, {Bao Cun} and Laursen, {Marlene F.} and Lili Hu and Hossein Hazrati and Ryo Narita and Jensen, {Lea S.} and Hansen, {Aida S.} and Jinrong Huang and Yan Zhang and Xiangning Ding and Maimaitili Muyesier and Emil Nilsson and Agnieszka Banasik and Christina Zeiler and Mogensen, {Trine H.} and Anders Etzerodt and Ralf Agger and Mogens Johannsen and Emil Kofod-Olsen and Paludan, {S{\o}ren R.} and Jakobsen, {Martin R.}",
note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",
year = "2024",
doi = "10.1038/s41467-024-47046-5",
language = "English",
volume = "15",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",
number = "1",

}

RIS

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