未折叠蛋白反应──细胞内信号传导新途径

Unfolded protein response

真核细胞中，当未折叠的蛋白在内质网上增多的时候，一系列内质网居民蛋白基因的转录也随之增加，这称为未折叠蛋白反应（ｕｎｆｏｌｄｅｄ ｐｒｏｔｅｉｎ ｒｅｓｐｏｎｓｅ， ＵＰＲ）。在酵母细胞中未折叠蛋白的感受器是Ｉｒｅｌｐ蛋白，它能检测到未折叠蛋白的聚集，并将信号传递到细胞核内，诱导ＵＰＲ特异转录因子Ｈａｃｌｐ ｍＲＮＡ的剪接成熟。成熟的 Ｈａｃ１ｐ蛋白能通过与 ＵＰＲ元件（ＵＰＲ－ｅｌｅｍｅｎｔ）的结合诱导含有这一元件的基因转录，从而启动 ＵＰＲ。在 ＵＰＲ信号传递途径中，磷酸化的 Ｉｒｅ１Ｐ与 Ｇｃｎ５／Ａｄａ复合物可通过解开染色体促进Ｈａｃ１ｐ活性的发挥；而Ｐｔｃ２ｐ能通过使Ｉｒｅｌｐ去磷酸化而反向调节ＵＰＲ。目前发现ＵＰＲ与磷脂生物合成存在交叉的共同途径，人类中也存在Ｉｒｅｌｐ的类似物。

Eukaryotic cells are characterized by the existence of many functionally distinct membrane-bound compartments or organelles. The endoplasmic reticulum (ER) is an organelle specialized for protein folding and assembly. When unfolded proteins accumulate in the ER, the transcription of a variety of genes encoding ER resident proteins is increased. This is called unfolded protein response (UPR). The Irelp is a receptor of unfolded protein in yeast. Irelp is a transmembrane kinase, it presumably detects the accumulation of unfolded proteins by unknown mechanism, and transfer the information to the nucleus by phosphorylation and oligomerization. When the information eliter the nucleus, the mRNA of the UPR-specific transcription factor Haclp begin splicing. The UPR-specific transcription factor Haclp has two kinds of mRNA, one lying in UPR induced cells named HAC1i mRNA, the other lying in uninduced cells named HAC1u mRNA. These two kinds of HAC1 mRNA are two splicing types only with a little difference, the HAC1i mRNA has an additional 252-nucleotides intervening sequence (IVS) at the 3' end. With this difference, the HAC1i mRNA can translate into functional protein and HAC1u mRNA can not translate because the lying of intron. Only when cells were induced to carry out UPR, the HAC1 mRNA could be spliced to HACli mRNA by a new unconventional splicing mechanism. In the UPR signaling pathway, Gcn5/Ada coactivator complex was recently identified as the required coactivators for the induction of the UPR. And the Ptc2p can work as a negative regulator of the UPR by dephosphorylation of Irelp. It was also found a functional human homologue of yeast Irelp, and a cross-talk between the UPR and phospholipid biosynthesis pathway.