ORMDL orosomucoid-like proteins are degraded by free-cholesterol-loading-induced autophagy

Proceedings of the National Academy of Sciences of the United States of America
Shuhui WangKailash Gulshan

Abstract

Eukaryotic cells have evolved robust mechanisms to counter excess cholesterol including redistribution of lipids into different compartments and compensatory up-regulation of phospholipid biosynthesis. We demonstrate here that excess cellular cholesterol increased the activity of the endoplasmic reticulum (ER) enzyme serine palmitoyl-CoA transferase (SPT), the rate-limiting enzyme in sphingomyelin synthesis. This increased SPT activity was not due to altered levels of SPTLC1 or SPTLC2, the major subunits of SPT. Instead, cholesterol loading decreased the levels of ORMDL1, a negative regulator of SPT activity, due to its increased turnover. Several lines of evidence demonstrated that free-cholesterol-induced autophagy, which led to increased turnover of ORMDL1. Cholesterol loading induced ORMDL1 redistribution from the ER to cytoplasmic p62 positive autophagosomes. Coimmunoprecipitation analysis of cholesterol-loaded cells showed increased association between ORMDL1 and p62. The lysosomal inhibitor chloroquine or siRNA knockdown of Atg7 inhibited ORMDL1 degradation by cholesterol, whereas proteasome inhibitors showed no effect. ORMDL1 degradation was specific to free-cholesterol loading as autophagy induced by serum starvation o...Continue Reading

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Citations

Jun 18, 2016·Journal of Lipid Research·Lin CaiSarah Spiegel
Jun 26, 2020·Frontiers in Cell and Developmental Biology·Yangchun XieDaolin Tang
Aug 4, 2019·The Journal of Allergy and Clinical Immunology·Briana JamesSarah Spiegel
Nov 5, 2020·BioMed Research International·Tengjiao ZhuYun Tian
Jul 10, 2021·Translational Oncology·Qian WangDaici Chen
Sep 9, 2018·Advances in Biological Regulation·Deanna DavisBinks Wattenberg

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