A survival pathway for Caenorhabditis elegans with a blocked unfolded protein response.
A survival pathway for Caenorhabditis elegans with a blocked unfolded protein response.
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DOI：
10.1083/jcb.200203086
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发表时间：
2002-08-19
期刊：
影响因子：
--
通讯作者：
Ron D
中科院分区：
文献类型：
--
作者：
Urano F;Calfon M;Yoneda T;Yun C;Kiraly M;Clark SG;Ron D
未折叠蛋白反应（UPR）抵消未加工的ER客户蛋白引起的压力。一项全基因组调查显示，xbp-1突变型秀丽隐杆线虫中许多UPR靶基因的诱导受损，这些基因无法在高度保守的IRE 1依赖性UPR途径中发出信号。然而，一个家族的基因，abu（激活阻断UPR），诱导ER应激xbp-1突变体动物比ER应激野生型动物更高的水平。RNA介导的干扰（RNAi）灭活一个代表性的abu家族成员，abu-1（AC3.3），激活ER应激标志物hsp-4：：gfp在其他正常动物和杀死50%的ER应激ire-1和xbp-1突变动物。Abu-1（RNAi）也增强了ER相关蛋白降解基因sel-1的失活效果。9个abu基因编码高度相关的I型跨膜蛋白，其内腔结构域与内皮细胞的哺乳动物细胞表面清道夫受体具有序列相似性，所述清道夫受体结合化学修饰的细胞外蛋白并指导其溶酶体降解。我们的研究结果表明，ABU-1是位于内膜系统内的细胞内蛋白质，在xbp-1突变动物中由ER应激诱导，这表明ABU蛋白可能与异常ER客户蛋白相互作用，并且这种功能在UPR受损的动物中可能特别重要。
The unfolded protein response (UPR) counteracts stress caused by unprocessed ER client proteins. A genome-wide survey showed impaired induction of many UPR target genes in xbp-1 mutant Caenorhabditis elegans that are unable to signal in the highly conserved IRE1-dependent UPR pathway. However a family of genes, abu (activated in blocked UPR), was induced to higher levels in ER-stressed xbp-1 mutant animals than in ER-stressed wild-type animals. RNA-mediated interference (RNAi) inactivation of a representative abu family member, abu-1 (AC3.3), activated the ER stress marker hsp-4::gfp in otherwise normal animals and killed 50% of ER-stressed ire-1 and xbp-1 mutant animals. Abu-1(RNAi) also enhanced the effect of inactivation of sel-1, an ER-associated protein degradation gene. The nine abu genes encode highly related type I transmembrane proteins whose lumenal domains have sequence similarity to a mammalian cell surface scavenger receptor of endothelial cells that binds chemically modified extracellular proteins and directs their lysosomal degradation. Our findings that ABU-1 is an intracellular protein located within the endomembrane system that is induced by ER stress in xbp-1 mutant animals suggest that ABU proteins may interact with abnormal ER client proteins and this function may be particularly important in animals with an impaired UPR.
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