中文摘要：

重组人细胞毒性T细胞相关抗原（Cytotoxic T Lymphocyte Associated Antigen 4,CTLA-4）是一类重要的基因工程药物,其在毕赤酵母中表达水平偏低使其一直无法广泛应用于临床治疗.而影响毕赤酵母中的外源蛋白分泌表达的因素,主要为内质网中的折叠速率以及不可折叠蛋白积累造成的胞内胁迫压力.本文通过在毕赤酵母细胞中过表达HAC1基因对毕赤酵母细胞中未折叠蛋白反应（Unfolded Protein Response,UPR）的信号通路进行调控,从而改善了CTLA-4蛋白的表达水平.摇瓶中改造菌株M-HAC1发酵上清液中该蛋白的分泌表达量是原始菌株表达量的2.55倍.

英文摘要：

Cytotoxic T Lymphocyte Associated Antigen 4 （CTLA-4）is a significant genetic engineering drug but unable to be widely used in clinic due to its low expression level in Pichia pastoris. The secretory expression of heterologous protein in Pichia pastoris is mainly influenced by two {actors that the folding rate of polypeptide in endoplasmic reticulum and the intraeellularstress eaused by the accumulation of unfolded proteins. However, HAC1, is regarded as a transcription factor of foldase in Pichia pastoris, whose overepression can accelerate its own folding rate by regulating the signal path of the unfolded protein response（UPR） which consequently improve the expression level of CTLA-4. Here, we demonstrate that the secretory expression level of CTLA-4 protein in the supernate of HACl-overexpressed strain M-HAC1 is increased by 2. 55 times.