Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment
Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment
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DOI：
10.1016/s0092-8674(00)81304-5
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发表时间：
1996-06-28
期刊：
影响因子：
64.5
通讯作者：
Goldstein, JL
中科院分区：
文献类型：
--
作者：
Sakai, J;Duncan, EA;Goldstein, JL
固醇调节元件结合蛋白(SREBPs)是与内质网结合的转录因子。激活转录的NH2-片段通过由两个跨膜序列和一个短腔环形成的发夹锚连接到膜上。利用H-RAS-SREBP-2融合蛋白，我们证明了NH2-片段是通过两次顺序切割从膜上释放出来的。第一种是由类固醇调节的，发生在管腔循环。第二个不受甾醇调节，发生在第一个跨膜区内。被释放的NH2片段进入细胞核，激活控制胆固醇合成和吸收的基因。某些突变的中国仓鼠卵巢细胞对胆固醇缺乏营养，因为它们不能进行第二次切割；NH2片段仍然与膜结合，转录没有激活。
Sterol regulatory element binding proteins (SREBPs) are transcription factors attached to the endoplasmic reticulum. The NH2-segment, which activates transcription, is connected to membranes by a hairpin anchor formed by two transmembrane sequences and a short lumenal loop. Using H-Ras-SREBP-2 fusion proteins, we show that the NH2-segment is released from membranes by two sequential cleavages. The first, regulated by sterols, occurs in the lumenal loop. The second, not regulated by sterols, occurs within the first transmembrane domain. The liberated NH2-segment enters the nucleus and activates genes controlling cholesterol synthesis and uptake. Certain mutant Chinese hamster ovary cells are auxotrophic for cholesterol because they fail to carry out the second cleavage; the NH2-segment remains membrane-bound and transcription is not activated.