title: Nogo-B receptor is necessary for cellular dolichol biosynthesis and protein N-glycosylation.
abstract: 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.
authors.affiliation: Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Harrison
authors.forename: Eon Joo
authors.initials: EJ
authors.lastname: Park
authors.forename: Ningguo
authors.initials: N
authors.lastname: Gao
authors.forename: Andrew
authors.initials: A
authors.lastname: Kuo
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Rush
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Waechter
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lehrman
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D002522:Chlorocebus aethiops; D004288:Dolichol Phosphates / Q000096:biosynthesis / Q000172:deficiency; D004286:Dolichols / Q000096:biosynthesis* / Q000172:deficiency; D004789:Enzyme Activation / Q000235:genetics; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000172:deficiency / Q000502:physiology*; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D004288:Dolichol Phosphates; D004286:Dolichols; D006023:Glycoproteins; C104585:NPC2 protein, human; C512614:NUS1 protein, human; D011956:Receptors, Cell Surface; D033921:Vesicular Transport Proteins; C028306:dolichol monophosphate; D019883:Alkyl and Aryl Transferases; C084921:cis-isoprenyltransferase