p31 Deficiency Influences Endoplasmic Reticulum Tubular Morphology and Cell Survival
p31 Deficiency Influences Endoplasmic Reticulum Tubular Morphology and Cell Survival
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DOI：
10.1128/mcb.01089-08
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发表时间：
2009-04-01
影响因子：
5.3
通讯作者：
Harada, Akihiro
中科院分区：
文献类型：
--
作者：
Uemura, Takefumi;Sato, Takashi;Harada, Akihiro
P31是酵母Use1p在哺乳动物中的同源物，是一种内质网(ER)定位的可溶性N-乙基马来酰亚胺敏感因子附着蛋白(SNAP)受体，它与其他SNARs，特别是Synaxin 18形成复合体。然而，p31在ER功能中的作用尚不清楚。为了确定p31在体内的作用，我们产生了p31条件基因敲除小鼠。我们发现，p31基因的纯合缺失导致了胚胎8.5天之前的早期胚胎死亡。在大脑和小鼠胚胎成纤维细胞(MEF)中条件性敲除p31导致大量细胞凋亡，同时伴随着内质网应激相关基因的上调。光镜分析显示，p31缺失细胞的内质网细胞膜出现囊泡并随后增大。到目前为止，这种类型的内质网小管的剧烈解体还没有被证明。这种明显的内质网结构变化先于内质网应激相关转录因子C/EBP同源蛋白(CHOP)的核转位，表明内质网应激诱导的细胞凋亡是由于内质网膜结构的破坏所致。综上所述，这些结果表明，p31是参与维持内质网形态的一个重要分子，它的缺失导致内质网应激诱导的细胞凋亡。
p31, the mammalian orthologue of yeast Use1p, is an endoplasmic reticulum (ER)-localized soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) that forms a complex with other SNAREs, particularly syntaxin 18. However, the role of p31 in ER function remains unknown. To determine the role of p31 in vivo, we generated p31 conditional knockout mice. We found that homozygous deletion of the p31 gene led to early embryonic lethality before embryonic day 8.5. Conditional knockout of p31 in brains and mouse embryonic fibroblasts (MEFs) caused massive apoptosis accompanied by upregulation of ER stress-associated genes. Microscopic analysis showed vesiculation and subsequent enlargement of the ER membrane in p31-deficient cells. This type of drastic disorganization in the ER tubules has not been demonstrated to date. This marked change in ER structure preceded nuclear translocation of the ER stress-related transcription factor C/EBP homologous protein (CHOP), suggesting that ER stress-induced apoptosis resulted from disruption of the ER membrane structure. Taken together, these results suggest that p31 is an essential molecule involved in the maintenance of ER morphology and that its deficiency leads to ER stress-induced apoptosis.