Nogo-B receptor is necessary for cellular dolichol biosynthesis and protein N-glycosylation

Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA.
The EMBO Journal (Impact Factor: 10.43). 06/2011; 30(12):2490-500. DOI: 10.1038/emboj.2011.147
Source: PubMed


Dolichol monophosphate (Dol-P) functions as an obligate glycosyl carrier lipid in protein glycosylation reactions. Dol-P is synthesized by the successive condensation of isopentenyl diphosphate (IPP), with farnesyl diphosphate catalysed by a cis-isoprenyltransferase (cis-IPTase) activity. Despite the recognition of cis-IPTase activity 40 years ago and the molecular cloning of the human cDNA encoding the mammalian enzyme, the molecular machinery responsible for regulating this activity remains incompletely understood. Here, we identify Nogo-B receptor (NgBR) as an essential component of the Dol-P biosynthetic machinery. Loss of NgBR results in a robust deficit in cis-IPTase activity and Dol-P production, leading to diminished levels of dolichol-linked oligosaccharides and a broad reduction in protein N-glycosylation. NgBR interacts with the previously identified cis-IPTase hCIT, enhances hCIT protein stability, and promotes Dol-P production. Identification of NgBR as a component of the cis-IPTase machinery yields insights into the regulation of dolichol biosynthesis.

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Available from: Charles J Waechter,
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    • "The association between the CPT and this ER-anchored protein has been suggested to form the functional dolichol synthase (Schenk et al., 2001; Harrison et al., 2011). Indeed RNAi-mediated knockdown of NgBR results in defective N– linked protein glycosylation and dolichol synthesis in animals, while knockout mutants of the yeast and plant orthologs are lethal (Yu et al., 2006; Zhang et al., 2008; Harrison et al., 2011). The fact that dehydrodolichyl diphosphate biosynthesis by a single eukaryotic protein has not been demonstrated in vitro, and that such an activity has only been recovered from microsomal membranes from animals, plants and yeast (Sakaihara et al., 2000; Shridas et al., 2003; Rush et al., 2010), suggests that eukaryotic dehydrodolichyl diphosphate synthases are evolutionarily conserved. "
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