Posttranslational negative regulation of glycosylated and non-glycosylated BCRP expression by Derlin-1.
Posttranslational negative regulation of glycosylated and non-glycosylated BCRP expression by Derlin-1.
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DOI：
10.1016/j.bbrc.2010.12.074
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发表时间：
2011-01-21
影响因子：
3.1
通讯作者：
Kai H
中科院分区：
文献类型：
--
作者：
Sugiyama T;Shuto T;Suzuki S;Sato T;Koga T;Suico MA;Kusuhara H;Sugiyama Y;Cyr DM;Kai H
人乳腺癌耐药蛋白(BCRP)/MXR/ABCG2是一种公认的ABC半转运蛋白，在许多正常组织和癌细胞的顶膜上高度表达。BCRP促进内源性和外源性有害外来物质的处置，以保护细胞/组织免受外来生物诱导的毒性。尽管BCRP在多种底物运输的生理和病理生理调节中有着巨大的影响，但人们对调节BCRP翻译后表达的因素知之甚少。在这里，我们确定了Derlin-1，一个与酵母Der1p具有同源性的蛋白质家族的成员，作为BCRP表达的翻译后调节因子。Derlin-1的过表达抑制了野生型(WT)BCRP从ER到高尔基体的运输，而野生型BCRP被认为是有效地运输到质膜上。另一方面，BCRP的N596Q突变体的蛋白表达被DERLIN-1的过表达强烈抑制，而DERLIN-1的敲除则稳定了N596Q蛋白的表达，这表明DERLIN-1对N596Q蛋白的表达具有负调控作用。值得注意的是，DERLIN-1的敲除也稳定了衣霉素诱导的脱糖化WT BCRP蛋白的表达，暗示糖基化状态对于DERLIN-1识别BCRP的重要性。因此，我们的数据表明DERLIN-1对糖基化和非糖化BCRP的表达都是负调节的，并提供了一种新的DERLIN-1对BCRP的翻译后调节机制。
Human breast cancer resistance protein (BCRP)/MXR/ABCG2 is a well-recognized ABC half-transporter that is highly expressed at the apical membrane of many normal tissues and cancer cells. BCRP facilitates disposition of endogenous and exogenous harmful xenobiotics to protect cells/tissues from xenobiotic-induced toxicity. Despite the enormous impact of BCRP in the physiological and pathophysiological regulation of the transport of a wide variety of substrates, little is known about the factors that regulate posttranslational expression of BCRP. Here, we identified Derlin-1, a member of a family of proteins that bears homology to yeast Der1p, as a posttranslational regulator of BCRP expression. Overexpression of Derlin-1 suppressed ER to Golgi transport of wild-type (WT) BCRP that is known to be efficiently trafficked to the plasma membrane. On the other hand, protein expression of N596Q variant of BCRP, N-linked glycosylation- deficient mutant that preferentially undergoes ubiquitin-mediated ER-associated degradation (ERAD), was strongly suppressed by the overexpression of Derlin-1, whereas knockdown of Derlin-1 stabilized N596Q protein, suggesting a negative regulatory role of Derlin-1 for N596Q protein expression. Notably, knockdown of Derlin-1 also stabilized the expression of tunicamycin-induced deglycosylated WT BCRP protein, implying the importance of glycosylation state for the recognition of BCRP by Derlin- 1. Thus, our data demonstrate that Derlin-1 is a negative regulator for both glycosylated and non-glycosylated BCRP expression and provide a novel posttranslational regulatory mechanism of BCRP by Derlin-1.
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影响因子：
6.8
作者：
Oldham, Michael L.;Davidson, Amy L.;Chen, Jue
通讯作者：
Chen, Jue
影响因子：
5.3
作者：
Taura, Manabu;Eguma, Ayaka;Kai, Hirofumi
通讯作者：
Kai, Hirofumi
DOI：
10.1016/j.bbrc.2010.09.132
发表时间：
2010-11-12
影响因子：
3.1
作者：
Shimasaki, Shogo;Koga, Tomoaki;Kai, Hirofumi
通讯作者：
Kai, Hirofumi
影响因子：
3.3
作者：
Bernardi, Kaleena M.;Williams, Jeffrey M.;Tsai, Billy
通讯作者：
Tsai, Billy
影响因子：
--
作者：
Turnbull EL;Rosser MF;Cyr DM
通讯作者：
Cyr DM