ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs
ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs
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DOI：
10.1016/s1097-2765(00)00133-7
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发表时间：
2000-12-01
期刊：
影响因子：
16
通讯作者：
Goldstein, JL
中科院分区：
文献类型：
--
作者：
Ye, J;Rawson, RB;Goldstein, JL
ATF6 是一种膜结合转录因子，可激活内质网 (ER) 应激反应中的基因。当未折叠的蛋白质在内质网中积累时，ATF6 被切割并释放其细胞质结构域，进入细胞核。在这里，我们表明 ATF6 由位点 1 蛋白酶 (S1P) 和位点 2 蛋白酶 (S2P) 加工，这些酶响应胆固醇剥夺而加工 SREBP。 ATF6 加工在缺乏 S2P 的细胞中被完全阻断，而在缺乏 S1P 的细胞中被部分阻断。 ATF6 处理需要 RxxL 和天冬酰胺/脯氨酸基序，分别是 S1P 和 S2P 处理的已知要求。缺乏 S2P 的细胞无法诱导 GRP78（ATF6 靶标）响应 ER 应激。 ATF6 处理不需要 SCAP，而 SCAP 对于 SREBP 处理至关重要。我们得出的结论是，S1P 和 S2P 是 ER 应激反应以及脂质合成所必需的。
ATF6 is a membrane-bound transcription factor that activates genes in the endoplasmic reticulum (ER) stress response. When unfolded proteins accumulate in the ER, ATF6 is cleaved to release its cytoplasmic domain, which enters the nucleus. Here, we show that ATF6 is processed by Site-1 protease (S1P) and Site-2 protease (S2P), the enzymes that process SREBPs in response to cholesterol deprivation. ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. ATF6 processing required the RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. ATF6 processing did not require SCAP, which is essential for SREBP processing. We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis.