Nature Cell Biology5, 781 - 792 (2003)
Published online: 10 August 2003; | doi:10.1038/ncb1035
The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages
Bo Feng1, Pin Mei Yao1, Yankun Li1, Cecilia M. Devlin1, Dajun Zhang1, Heather P. Harding2, Michele Sweeney3, James X. Rong4, George Kuriakose1, Edward A. Fisher4, Andrew R. Marks3, David Ron2
& Ira Tabas1
1
Departments of Medicine and Cell Biology, Columbia University, New York, NY 10032, USA.
2
Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
3
Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, Columbia University, New York, NY 10032, USA.
4
Department of Medicine and The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
Excess cellular cholesterol induces apoptosis in macrophages, an event likely to promote progression of atherosclerosis. The cellular mechanism of cholesterol-induced apoptosis is unknown but had previously been thought to involve the plasma membrane. Here we report that the unfolded protein response (UPR) in the endoplasmic reticulum is activated in cholesterol-loaded macrophages, resulting in expression of the cell death effector CHOP. Cholesterol loading depletes endoplasmic reticulum calcium stores, an event known to induce the UPR. Furthermore, endoplasmic reticulum calcium depletion, the UPR, caspase-3 activation and apoptosis are markedly inhibited by selective inhibition of cholesterol trafficking to the endoplasmic reticulum, and Chop-/- macrophages are protected from cholesterol-induced apoptosis. We propose that cholesterol trafficking to endoplasmic reticulum membranes, resulting in activation of the CHOP arm of the UPR, is the key signalling step in cholesterol-induced apoptosis in macrophages.
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