Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins.

Nature Immunology
Quan D ZhouSteven J Bensinger

Abstract

Plasma membranes of animal cells are enriched for cholesterol. Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins secreted by bacteria that target membrane cholesterol for their effector function. Phagocytes are essential for clearance of CDC-producing bacteria; however, the mechanisms by which these cells evade the deleterious effects of CDCs are largely unknown. Here, we report that interferon (IFN) signals convey resistance to CDC-induced pores on macrophages and neutrophils. We traced IFN-mediated resistance to CDCs to the rapid modulation of a specific pool of cholesterol in the plasma membrane of macrophages without changes to total cholesterol levels. Resistance to CDC-induced pore formation requires the production of the oxysterol 25-hydroxycholesterol (25HC), inhibition of cholesterol synthesis and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking the ability of IFN to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage. These studies illuminate targeted regulation of membrane cholesterol content as a host defense strategy.

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Citations

Sep 16, 2020·Traffic·Yvonne Lange, Theodore L Steck
Jun 10, 2020·Nature Immunology·Eric V DangRussell E Vance
Jan 26, 2021·Biochemical Society Transactions·Pratima VermaKausik Chattopadhyay
Feb 12, 2021·International Journal of Molecular Sciences·David Alexander Christian MessererMarkus Huber-Lang
Feb 10, 2021·Journal of Cell Science·Lena Pernas
Feb 2, 2021·Endocrine Reviews·Adil Rasheed, Katey J Rayner
May 16, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Mateusz PospiechI Martin Sheldon
Jun 22, 2021·Journal of Cell Science·Heidrun SteinleThomas A Kufer
Sep 28, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Thomas J R OrmsbyIain M Sheldon
Oct 13, 2021·Journal of the American Society for Mass Spectrometry·Baolong SuKevin J Williams

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Methods Mentioned

BETA
PCR
flow cytometry
scraping
FACS

Software Mentioned

GraphPad Prism
Prism
Zen
Powercore
ggplot2
ImageJ
MetaXpress
R

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