Welihinda A A, Tirasophon W, Kaufman R J
Department of Biological Chemistry, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0650, USA.
J Biol Chem. 2000 Feb 4;275(5):3377-81. doi: 10.1074/jbc.275.5.3377.
Accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates signaling pathways to induce transcription of a number of genes encoding ER protein chaperones and-folding catalysts. In Saccharomyces cerevisiae this transcriptional induction is mediated by an increase in the synthesis of the transcription factor Hac1p. The transmembrane receptor Ire1p/Ern1p containing a Ser/Thr protein kinase and endoribonuclease activity transmits the unfolded protein response (UPR) from the ER to the nucleus. Activation of Ire1p kinase induces its endoribonuclease activity to cleave unspliced HAC1 mRNA and generate exon fragments that are subsequently ligated by tRNA ligase (RLG1). Whereas unspliced HAC1 mRNA is poorly translated, spliced HAC1 mRNA is efficiently translated. Subunits of the yeast transcriptional co-activator complex SAGA also play a role in the UPR. Deletion of GCN5, ADA2, or ADA3 reduces, and deletion of ADA5 completely abolishes, the UPR. Although HAC1 mRNA requires only Ire1p and Rlg1p in vitro, we demonstrate that ADA5 is required for the IRE1/RLG1-dependent splicing reaction of HAC1 mRNA in vivo. In addition, Ada5p interacts with Ire1p. These results suggest that subcomponents of transcriptional co-activator complexes may be involved in RNA processing events.
内质网（ER）中未折叠蛋白的积累会激活信号通路，从而诱导许多编码ER蛋白伴侣和折叠催化剂的基因转录。在酿酒酵母中，这种转录诱导是由转录因子Hac1p合成增加介导的。含有丝氨酸/苏氨酸蛋白激酶和核糖核酸内切酶活性的跨膜受体Ire1p/Ern1p将未折叠蛋白反应（UPR）从内质网传递到细胞核。Ire1p激酶的激活会诱导其核糖核酸内切酶活性，切割未剪接的HAC1 mRNA并产生外显子片段，随后这些片段由tRNA连接酶（RLG1）连接。未剪接的HAC1 mRNA翻译效率低，而剪接后的HAC1 mRNA则能有效翻译。酵母转录共激活因子复合物SAGA的亚基在UPR中也发挥作用。缺失GCN5、ADA2或ADA3会降低UPR，而缺失ADA5则会完全消除UPR。尽管HAC1 mRNA在体外仅需要Ire1p和Rlg1p，但我们证明ADA5在体内是HAC1 mRNA依赖IRE1/RLG1的剪接反应所必需的。此外，Ada5p与Ire1p相互作用。这些结果表明转录共激活因子复合物的亚组分可能参与RNA加工事件。
