PT  - JOURNAL ARTICLE
AU  - David B. Heisler
AU  - Kristen A. Johnson
AU  - Maikke B. Ohlson
AU  - Duo Ma
AU  - Lishu Zhang
AU  - Michelle Tran
AU  - Chase D. Corley
AU  - Michael E. Abrams
AU  - Jeffrey G. McDonald
AU  - John W. Schoggins
AU  - Neal M. Alto
AU  - Arun Radhakrishnan
TI  - A Concerted Mechanism Involving ACAT and SREBPs By which Oxysterols Deplete Accessible Cholesterol To Restrict Microbial Infection
AID  - 10.1101/2022.10.10.510128
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.10.10.510128
4099  - http://biorxiv.org/content/early/2022/10/11/2022.10.10.510128.short
4100  - http://biorxiv.org/content/early/2022/10/11/2022.10.10.510128.full
AB  - Most of the cholesterol in the plasma membranes (PMs) of animal cells is sequestered through interactions with phospholipids and transmembrane domains of proteins. However, as cholesterol concentration rises above the PM’s sequestration capacity, a new pool of cholesterol, called accessible cholesterol, emerges. The transport of accessible cholesterol between the PM and the endoplasmic reticulum (ER) is critical to maintain cholesterol homeostasis. This pathway has also been implicated in the suppression of both bacterial and viral pathogens by immunomodulatory oxysterols. Here, we describe a mechanism of depletion of accessible cholesterol from PMs by the oxysterol 25-hydroxycholesterol (25HC). We show that 25HC-mediated activation of acyl coenzyme A: cholesterol acyltransferase (ACAT) in the ER creates an imbalance in the equilibrium distribution of accessible cholesterol between the ER and PM. This imbalance triggers the rapid internalization of accessible cholesterol from the PM, which is sustained for long periods of time through 25HC-mediated suppression of SREBPs. In support of a physiological role for this mechanism, 25HC failed to suppress Zika virus and human coronavirus infection in ACAT-deficient cells, and Listeria monocytogenes infection in ACAT-deficient cells and mice. We propose that selective depletion of accessible PM cholesterol triggered by ACAT activation and sustained through SREBP suppression underpins the immunological activities of 25HC and a functionally related class of oxysterols.Competing Interest StatementThe authors have declared no competing interest.