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 PaludanMartin R Jakobsen

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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.

OriginalsprogEngelsk
Artikelnummer2760
TidsskriftNature Communications
Vol/bind15
Nummer1
Sider (fra-til)2760
ISSN2041-1723
DOI
StatusUdgivet - 29 mar. 2024

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