Targeting of neutral cholesterol ester hydrolase to the endoplasmic reticulum via its N-terminal sequence |
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Authors: | Masaki Igarashi Jun-ichi Osuga Masashi Isshiki Motohiro Sekiya Hiroaki Okazaki Satoru Takase Mikio Takanashi Keisuke Ohta Masayoshi Kumagai Makiko Nishi Toshiro Fujita Ryozo Nagai Takashi Kadowaki Shun Ishibashi |
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Institution: | 4. Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;2. Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine, Jichi Medical University, Tochigi 329-0498, Japan |
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Abstract: | Neutral cholesterol ester hydrolase (NCEH) accounts for a large part of the nCEH activity in macrophage foam cells, a hallmark of atherosclerosis, but its subcellular localization and structure-function relationship are unknown. Here, we determined subcellular localization, glycosylation, and nCEH activity of a series of NCEH mutants expressed in macrophages. NCEH is a single-membrane-spanning type II membrane protein comprising three domains: N-terminal, catalytic, and lipid-binding domains. The N-terminal domain serves as a type II signal anchor sequence to recruit NCEH to the endoplasmic reticulum (ER) with its catalytic domain within the lumen. All of the putative N-linked glycosylation sites (Asn270, Asn367, and Asn389) of NCEH are glycosylated. Glycosylation at Asn270, which is located closest to the catalytic serine motif, is important for the enzymatic activity. Cholesterol loading by incubation with acetyl-LDL does not change the ER localization of NCEH. In conclusion, NCEH is targeted to the ER of macrophages, where it hydrolyzes CE to deliver cholesterol for efflux out of the cells. |
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Keywords: | macrophage atherosclerosis lipid droplets foam cells glycosylation cholesterol efflux type II membrane protein vesicular transport KIAA1363 arylacetamide deacetylase like 1 |
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