Mannosidase 2, alpha 1 Deficiency Is Associated with Ricin Resistance in Embryonic Stem (ES) Cells

被引：46

作者：

Wang, Wei ^{[1
]}

Hale, Christine ^{[1
]}

Goulding, Dave ^{[1
]}

Haslam, Stuart M. ^{[2
]}

Tissot, Berangere ^{[2
]}

Lindsay, Christopher ^{[3
]}

Michell, Stephen ^{[4
]}

Titball, Rick ^{[4
]}

Yu, Jun ^{[5
]}

Toribio, Ana Luisa ^{[1
]}

Rossi, Raffaella ^{[1
]}

Dell, Anne ^{[2
]}

Bradley, Allan ^{[1
]}

Dougan, Gordon ^{[1
]}

机构：

[1] Wellcome Trust Sanger Inst, Hinxton, Cambs, England

[2] Univ London Imperial Coll Sci Technol & Med, Div Mol Biosci, London, England

[3] Dept Biomed Sci, Cellular Tox Team, Salisbury, Wilts, England

[4] Univ Exeter, Sch Biosci, Exeter, Devon, England

[5] Univ Strathclyde, Royal Coll, Strathclyde Inst Pharm & Biomed Sci, Glasgow, Lanark, Scotland

来源：

PLOS ONE | 2011年 / 6卷 / 08期

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

RIBOSOME-INACTIVATING PROTEINS; GLYCANS; GLYCOPROTEINS; TRANSPORT; PIGGYBAC; LIBRARY;

D O I：

10.1371/journal.pone.0022993

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Host gene products required for mediating the action of toxins are potential targets for reversing or controlling their pathogenic impact following exposure. To identify such targets libraries of insertional gene-trap mutations generated with a PiggyBac transposon in Blm-deficient embryonic stem cells were exposed to the plant toxin, ricin. Resistant clones were isolated and genetically characterised and one was found to be a homozygous mutant of the mannosidase 2, alpha 1 (Man2 alpha 1) locus with a matching defect in the homologous allele. The causality of the molecular lesion was confirmed by removal of the transposon following expression of PB-transposase. Comparative glycomic and lectin binding analysis of the Man2 alpha 1 (-/-) ricin resistant cells revealed an increase in the levels of hybrid glycan structures and a reduction in terminal beta-galactose moieties, potential target receptors for ricin. Furthermore, naive ES cells treated with inhibitors of the N-linked glycosylation pathway at the mannosidase 2, alpha 1 step exhibited either full or partial resistance to ricin. Therefore, we conclusively identified mannosidase 2, alpha 1 deficiency to be associated with ricin resistance.

引用

页数：13

共 33 条

[1] Essential and mutually compensatory roles of α-mannosidase II and α-mannosidase IIx in N-glycan processing in vivo in mice [J].