ATF6alpha induces XBP1-independent expansion of the endoplasmic reticulum.
ATF6alpha induces XBP1-independent expansion of the endoplasmic reticulum.
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DOI：
10.1242/jcs.045625
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发表时间：
2009-05-15
影响因子：
4
通讯作者：
Brewer JW
中科院分区：
文献类型：
--
作者：
Bommiasamy H;Back SH;Fagone P;Lee K;Meshinchi S;Vink E;Sriburi R;Frank M;Jackowski S;Kaufman RJ;Brewer JW
内质网（ER）生物发生与未折叠蛋白反应（UPR）之间存在联系，UPR是一组复杂的信号机制，由内质网蛋白质折叠能力的需求增加引发。UPR转录激活因子X-box结合蛋白1 （XBP1）调节在整个分泌途径中起作用的蛋白的表达，并且是扩展内质网发展所必需的。我们之前已经证明过表达XBP1(S) （XBP1的活性形式，由upr介导的XBP1 mRNA剪接产生），可以增强胞苷二磷酸胆碱（cdp -胆碱）途径的活性，从而促进磷脂酰胆碱（PtdCho）的生物合成，并诱导内质网的生物发生。另一种UPR转录激活因子，激活转录因子6α (ATF6α)，主要调控内质网驻留蛋白的表达，参与内质网客户蛋白的成熟和降解。在这里，我们证明了一种本构活性形式的ATF6α的强制表达驱动内质网扩张，并且可以在没有XBP1(S)的情况下这样做。活性ATF6α的过表达诱导PtdCho生物合成和调节cdp -胆碱途径不同于XBP1的强制表达(S)。这些数据表明，ATF6α和XBP1(S)能够通过至少部分不同的机制调节脂质生物合成和内质网扩张。这些研究进一步揭示了UPR通路、脂质产生和内质网生物发生之间潜在关系的复杂性。
A link exists between endoplasmic reticulum (ER) biogenesis and the unfolded protein response (UPR), a complex set of signaling mechanisms triggered by increased demands on the protein folding capacity of the ER. The UPR transcriptional activator X-box binding protein 1 (XBP1) regulates the expression of proteins that function throughout the secretory pathway and is necessary for development of an expansive ER network. We previously demonstrated that overexpression of XBP1(S), the active form of XBP1 generated by UPR-mediated splicing of Xbp1 mRNA, augments the activity of the cytidine diphosphocholine (CDP-choline) pathway for biosynthesis of phosphatidylcholine (PtdCho) and induces ER biogenesis. Another UPR transcriptional activator, activating transcription factor 6α (ATF6α), primarily regulates expression of ER resident proteins involved in the maturation and degradation of ER client proteins. Here, we demonstrate that enforced expression of a constitutively active form of ATF6α drives ER expansion and can do so in the absence of XBP1(S). Overexpression of active ATF6α induces PtdCho biosynthesis and modulates the CDP-choline pathway differently than does enforced expression of XBP1(S). These data indicate that ATF6α and XBP1(S) have the ability to regulate lipid biosynthesis and ER expansion by mechanisms that are at least partially distinct. These studies reveal further complexity in the potential relationships between UPR pathways, lipid production and ER biogenesis.
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