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

Bao-Cun Zhang; Marlene F Laursen; Lili Hu; Hossein Hazrati; Ryo Narita; Lea S Jensen; Aida S Hansen; Jinrong Huang; Yan Zhang; Xiangning Ding; Maimaitili Muyesier; Emil Nilsson; Agnieszka Banasik; Christina Zeiler; Trine H Mogensen; Anders Etzerodt; Ralf Agger; Mogens Johannsen; Emil Kofod-Olsen; Søren R Paludan; Martin R Jakobsen

doi:10.1038/s41467-024-47046-5

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

Bao-Cun Zhang^*, Marlene F Laursen, Lili Hu, Hossein Hazrati, Ryo Narita, Lea S Jensen, Aida S Hansen, Jinrong Huang, Yan Zhang, Xiangning Ding, Maimaitili Muyesier, Emil Nilsson, Agnieszka Banasik, Christina Zeiler, Trine H Mogensen, Anders Etzerodt, Ralf Agger, Mogens Johannsen, Emil Kofod-Olsen, Søren R Paludan^*Martin R Jakobsen^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

15 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	2760
Tidsskrift	Nature Communications
Vol/bind	15
Nummer	1
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-024-47046-5
Status	Udgivet - dec. 2024

Adgang til dokumentet

10.1038/s41467-024-47046-5Licens: CC BY

Andre filer og links

Link to publication in Scopus

Citationsformater

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), Artikel 2760. https://doi.org/10.1038/s41467-024-47046-5

@article{d04ce01487e041ffa1c8ec907cb98de5,

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.",

keywords = "Humans, Membrane Proteins/metabolism, Signal Transduction/physiology, Interferons/metabolism, Nucleotidyltransferases/metabolism, Neoplasms/therapy, Endoplasmic Reticulum/metabolism, Tumor Microenvironment",

author = "Bao-Cun Zhang 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}",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-47046-5",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Zhang, B-C, 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

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 et al.
I: Nature Communications, Bind 15, Nr. 1, 2760, 12.2024.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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

PY - 2024/12

Y1 - 2024/12

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.

KW - Humans

KW - Membrane Proteins/metabolism

KW - Signal Transduction/physiology

KW - Interferons/metabolism

KW - Nucleotidyltransferases/metabolism

KW - Neoplasms/therapy

KW - Endoplasmic Reticulum/metabolism

KW - Tumor Microenvironment

UR - http://www.scopus.com/inward/record.url?scp=85189018234&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-47046-5

DO - 10.1038/s41467-024-47046-5

M3 - Journal article

C2 - 38553448

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2760

ER -

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

Abstract

Adgang til dokumentet

Andre filer og links

Fingeraftryk

Citationsformater