Deletion of SERP1/RAMP4, a component of the endoplasmic reticulum (ER) translocation sites, leads to ER stress
Deletion of SERP1/RAMP4, a component of the endoplasmic reticulum (ER) translocation sites, leads to ER stress
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DOI：
10.1128/mcb.02055-05
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发表时间：
2006-06-01
影响因子：
5.3
通讯作者：
Ogawa, Satoshi
中科院分区：
文献类型：
--
作者：
Hori, Osamu;Miyazaki, Mayuki;Ogawa, Satoshi
应激相关内质网（ER）蛋白1（SERP 1），也称为核糖体相关膜蛋白4（RAMP 4），是由ER应激诱导的Sec 61相关多肽。通过靶向基因破坏产生的SERP 1（-/-）小鼠表现出生长迟缓、死亡率增加和葡萄糖耐量受损。与胰腺中高水平的SERP 1表达一致，来自SERP 1（-/-）小鼠的胰岛不能响应于葡萄糖负荷快速合成胰岛素原。此外，在SERP 1（-/-）小鼠的垂体前叶中观察到体积减小和增强的ER应激，并且在胰岛素刺激后SERP 1-/-垂体中生长激素的产生减慢。使用胰腺微粒体的实验揭示了SERP 1（-/-）胰腺中核糖体和Sec 61复合物的异常结合和增强的ER应激。在基础条件下，与高盐条件下的SERP 1（-/-）对应物相比，SERP 1（-/-）微粒体中的Sec 61复合物更多地与核糖体共分馏。相反，葡萄糖刺激后，复合物在早期（45分钟）表现出较少的共分馏，但在后期（120分钟）更多。虽然细胞内胰岛素/胰岛素原水平在两种基因型中没有显着变化，这些结果表明，易位效率的微妙变化在ER应激和快速多肽合成的调节中起着重要作用。
Stress-associated endoplasmic reticulum (ER) protein 1 (SERP1), also known as ribosome-associated membrane protein 4 (RAMP4), is a Sec61-associated polypeptide that is induced by ER stress. SERP1(-/-) mice, made by targeted gene disruption, demonstrated growth retardation, increased mortality, and impaired glucose tolerance. Consistent with high levels of SERP1 expression in pancreas, pancreatic islets from SERP1(-/-) mice failed to rapidly synthesize proinsulin in response to a glucose load. In addition, reduced size and enhanced ER stress were observed in the anterior pituitary of SERP1(-/-) mice, and growth hormone production was slowed in SERPI-/- pituitary after insulin stimulation. Experiments using pancreatic microsomes revealed aberrant association of ribosomes and the Sec61 complex and enhanced ER stress in SERP1(-/-) pancreas. In basal conditions, the Sec61 complex in SERP1(-/-) microsomes was more cofractionated with ribosomes, compared with SERP1(-/-) counterparts, in high-salt conditions. In contrast, after glucose stimulation, the complex showed less cofractionation at an early phase (45 min) but more at a later phase (120 min). Although intracellular insulin/proinsulin levels were not significantly changed in both genotypes, these results suggest that subtle changes in translocation efficiency play an important role in the regulation of ER stress and rapid polypeptide synthesis.