open access publication

Article, 2024

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

Nature Communications, ISSN 2041-1723, Volume 15, 1, Page 2760, 10.1038/s41467-024-47046-5

Contributors

Zhang, Bao-Cun 0000-0001-6104-0848 (Corresponding author) [1] Laursen, Marlene Fyrstenberg 0000-0002-2804-0026 [2] Hu, Lili [1] Hazrati, Hossein 0000-0001-5343-5866 [1] Narita, Ryo [1] Jensen, Lea S [1] Hansen, Aida Solhøj 0000-0002-6547-8393 [1] Huang, Jinrong 0000-0001-8085-9939 [3] Zhang, Yan 0000-0002-9173-7029 [1] Ding, Xiangning [1] Muyesier, Maimaitili [1] Nilsson, Emil [1] Banasik, Agnieszka [2] Zeiler, Christina [2] Mogensen, Trine Hyrup 0000-0002-1853-9704 [1] [4] Etzerodt, Anders 0000-0002-6757-2068 [1] Agger, Ralf [2] Johannsen, Mogens 0000-0002-2548-7025 [1] Kofod-Olsen, Emil 0000-0003-2918-8978 [2] Paludan, Søren Riis 0000-0001-9180-4060 (Corresponding author) [1] Jakobsen, Martin Roelsgaard (Corresponding author) [1]

Affiliations

  1. [1] Aarhus University
    2. [NORA names: AU Aarhus University; University; Denmark; Europe, EU; Nordic; OECD];
  2. [2] Aalborg University
    3. [NORA names: AAU Aalborg University; University; Denmark; Europe, EU; Nordic; OECD];
  3. [3] University of Copenhagen
    4. [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD];
  4. [4] Aarhus University Hospital
    5. [NORA names: Central Denmark Region; Hospital; Denmark; Europe, EU; Nordic; OECD]

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

ER cholesterol, ER retention, Golgi, STING pathway activation, STING signaling, active inflammation, activity, anti-PD-1 antibody, anti-tumor activity, anti-tumor responses, antibodies, assembly, cGAMP, cGAMP stimulation, cGAS-STING, cGAS-STING pathway, cancer, cancer immunotherapy, cholesterol, cholesterol esterification, cholesterol levels, cholesterol-binding motifs, cholesterol-lowering compounds, combination, complex assembly, compounds, curvature, cytokines, decline, depletion, endoplasmic reticulum, endoplasmic reticulum retention, esterification, immunotherapy, induction, induction of interferon, inflammation, inflammatory cytokines, interferon, intracellular cholesterol levels, intratumorally, levels, membrane curvature, microenvironment, model, motif, pathway, pathway activation, preclinical tumor models, remission, response, retention, reticulum, signal, signaling complex assembly, sterols, stimulation, stings, threshold, transient decline, tumor, tumor microenvironment, tumor model, tumor remission

Funders

  • European Research Council
  • Lundbeck Foundation
  • Danish Cancer Society
  • Novo Nordisk Foundation

Data Provider: Digital Science

LINKS
-

Matching Records in NORA

SUBJECTS
+

METRICS
+