Adaptation of endoplasmic reticulum exit sites to acute and chronic increases in cargo load
Adaptation of endoplasmic reticulum exit sites to acute and chronic increases in cargo load
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DOI：
10.1038/emboj.2008.136
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发表时间：
2008-08-06
期刊：
影响因子：
11.4
通讯作者：
Hauri, Hans-Peter
中科院分区：
文献类型：
--
作者：
Farhan, Hesso;Weiss, Matthias;Hauri, Hans-Peter
内质网（ER）出口位点（ERES）的生物发生涉及磷脂酰肌醇-4磷酸（PI 4）和Sec 16的形成，但ERES如何适应货物负荷的变化是完全未知的。在这里，我们研究了急性和慢性适应性反应的ERES货物负荷ER出口的增加。急性反应（在几分钟内）增加货物负荷刺激ERES融合事件，导致更大，但更少的ERES。沉默PI 4-激酶III α（PI 4K-III α）或Sec 16抑制急性反应。过表达分泌货物24小时诱导未折叠蛋白反应（UPR），上调COPII，细胞形成更多的ERES。这种慢性反应对沉默PI 4K-III α不敏感，但通过沉默Sec 16而消除。UPR是必需的，因为缺乏肌醇需要蛋白1的细胞中不存在慢性反应。数学模型模拟进一步支持了这样的观点，即增加ERES数量以及COPII水平是提高分泌通量的有效方法。这些结果表明，货物负荷的慢性和急性增加处理差异ERES和不同的因素进行调节。
The biogenesis of endoplasmic reticulum (ER) exit sites (ERES) involves the formation of phosphatidylinositol-4 phosphate (PI4) and Sec16, but it is entirely unknown how ERES adapt to variations in cargo load. Here, we studied acute and chronic adaptive responses of ERES to an increase in cargo load for ER export. The acute response (within minutes) to increased cargo load stimulated ERES fusion events, leading to larger but less ERES. Silencing either PI4-kinase III alpha (PI4K-III alpha) or Sec16 inhibited the acute response. Overexpression of secretory cargo for 24 h induced the unfolded protein response (UPR), upregulated COPII, and the cells formed more ERES. This chronic response was insensitive to silencing PI4K-III alpha, but was abrogated by silencing Sec16. The UPR was required as the chronic response was absent in cells lacking inositol-requiring protein 1. Mathematical model simulations further support the notion that increasing ERES number together with COPII levels is an efficient way to enhance the secretory flux. These results indicate that chronic and acute increases in cargo load are handled differentially by ERES and are regulated by different factors.