趙運(yùn)英， 王 頔， 袁 凡， 蔣伶活

(江南大學(xué)生物工程學(xué)院 糧食發(fā)酵工藝與技術(shù)國(guó)家工程實(shí)驗(yàn)室, 江蘇 無(wú)錫 214122)

釀酒酵母細(xì)胞中內(nèi)質(zhì)網(wǎng)應(yīng)激與未折疊蛋白反應(yīng)的研究進(jìn)展

趙運(yùn)英， 王 頔， 袁 凡， 蔣伶活*

(江南大學(xué)生物工程學(xué)院 糧食發(fā)酵工藝與技術(shù)國(guó)家工程實(shí)驗(yàn)室, 江蘇 無(wú)錫 214122)

內(nèi)質(zhì)網(wǎng)應(yīng)激激活的未折疊蛋白反應(yīng)(Unfolded protein response，UPR)途徑在釀酒酵母和哺乳動(dòng)物細(xì)胞中是非常保守的。內(nèi)質(zhì)網(wǎng)(Endoplasmic reticulum，ER)是蛋白質(zhì)合成、折疊和修飾的細(xì)胞器，也是貯存鈣的主要場(chǎng)所之一。酵母細(xì)胞內(nèi)質(zhì)網(wǎng)鈣平衡與UPR的作用是相互的；兩個(gè)MAPK途徑——HOG途徑和CWI途徑都是細(xì)胞應(yīng)答內(nèi)質(zhì)網(wǎng)應(yīng)激壓力時(shí)生存所必需的；重金屬鎘離子能夠激活UPR途徑，它通過(guò)激活鈣離子通道Cch1/Mid1進(jìn)入細(xì)胞影響鈣離子的功能。本文結(jié)合最新研究進(jìn)展對(duì)釀酒酵母細(xì)胞中的兩個(gè)MAPK途徑、鎘離子和鈣離子穩(wěn)態(tài)與內(nèi)質(zhì)網(wǎng)應(yīng)激激活的UPR途徑之間相互關(guān)系進(jìn)行綜述。

未折疊蛋白反應(yīng)；內(nèi)質(zhì)網(wǎng)應(yīng)激；MAPK；鈣離子信號(hào)途徑；釀酒酵母

細(xì)胞應(yīng)激涉及線粒體、內(nèi)質(zhì)網(wǎng)和細(xì)胞核的應(yīng)激。內(nèi)質(zhì)網(wǎng)(Endoplasmic reticulum，ER)是蛋白質(zhì)合成、折疊和修飾的細(xì)胞器，也是貯存鈣的主要場(chǎng)所之一。內(nèi)質(zhì)網(wǎng)功能的紊亂會(huì)導(dǎo)致未折疊蛋白在內(nèi)質(zhì)網(wǎng)腔內(nèi)積累及其腔內(nèi)鈣穩(wěn)態(tài)的破壞。缺氧、營(yíng)養(yǎng)缺乏、氧化還原狀態(tài)的破壞、異常的鈣離子調(diào)節(jié)、病毒感染、蛋白翻譯后修飾發(fā)生故障或者內(nèi)質(zhì)網(wǎng)中未折疊或錯(cuò)誤折疊蛋白質(zhì)的積累均可導(dǎo)致內(nèi)質(zhì)網(wǎng)應(yīng)激(Endoplasmic reticulum stress，ER stress)[1-5]。內(nèi)質(zhì)網(wǎng)應(yīng)激與許多人類疾病的發(fā)生和發(fā)展密切相關(guān)，如癌癥、糖尿病、炎性疾病以及神經(jīng)系統(tǒng)、腎臟、肺和心血管疾病等[6-10]。許多研究證明癌細(xì)胞可以抵抗極端的環(huán)境壓力，可能是由于癌細(xì)胞改變了內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)的正常狀態(tài)[11]。釀酒酵母作為一種模式生物，被廣泛用于科學(xué)研究。內(nèi)質(zhì)網(wǎng)應(yīng)激激活的未折疊蛋白反應(yīng)(Unfolded protein response，UPR)途徑在釀酒酵母和哺乳動(dòng)物細(xì)胞中是非常保守的。本文將論述釀酒酵母細(xì)胞中內(nèi)質(zhì)網(wǎng)應(yīng)激與未折疊蛋白反應(yīng)的最新研究進(jìn)展。

1 酵母細(xì)胞中內(nèi)質(zhì)網(wǎng)應(yīng)激和UPR概述

1.1 酵母細(xì)胞和哺乳動(dòng)物細(xì)胞的UPR組分

內(nèi)質(zhì)網(wǎng)壓力是指未折疊蛋白在內(nèi)質(zhì)網(wǎng)內(nèi)積累，從而誘導(dǎo)一種可適應(yīng)性程序稱作未折疊蛋白反應(yīng)。內(nèi)質(zhì)網(wǎng)應(yīng)激激活的UPR反應(yīng)是1988年由Kozutsumi等人觀察到的非折疊蛋白反應(yīng)[12]。后來(lái)通過(guò)酵母遺傳學(xué)研究發(fā)現(xiàn)了決定UPR反應(yīng)的蛋白因子，UPR這一獨(dú)特的細(xì)胞反應(yīng)才得到普遍的認(rèn)可[13-14]。釀酒酵母內(nèi)質(zhì)網(wǎng)膜上的跨膜蛋白Ire1(Inositol requiring enzyme 1)是一種核酸內(nèi)切酶。在無(wú)內(nèi)質(zhì)網(wǎng)應(yīng)激條件下，Ire1的內(nèi)質(zhì)網(wǎng)腔內(nèi)結(jié)構(gòu)域與內(nèi)質(zhì)網(wǎng)內(nèi)的分子伴侶蛋白Grp38結(jié)合[15]。當(dāng)錯(cuò)誤折疊或者未折疊蛋白聚集時(shí)，Grp38轉(zhuǎn)而與這些蛋白結(jié)合，Ire1得到釋放并激活，形成聚合體，非常規(guī)地剪接胞質(zhì)內(nèi)無(wú)翻譯活性的HAC1 mRNA[16-17](圖1a，表1)。剪接后的HAC1 mRNA被翻譯為轉(zhuǎn)錄因子蛋白Hac1，Hac1進(jìn)入細(xì)胞核中結(jié)合靶基因啟動(dòng)子上的UPR元件，誘導(dǎo)靶基因的表達(dá)，以緩解錯(cuò)誤折疊或者未折疊蛋白造成的內(nèi)質(zhì)網(wǎng)應(yīng)激壓力。這些靶基因的啟動(dòng)子上都含有UPR元件，包括KAR2、PDI1、EUG1、FKB2、LHS1、AIM17、ERJ5、FIT2、FIT3、FRE1、GAS5、HXT9、KEG1、LDB17、MTR10、SIL1、TAD2和VPS17等內(nèi)質(zhì)網(wǎng)應(yīng)答相關(guān)基因[18-20]。

在哺乳動(dòng)物的內(nèi)質(zhì)網(wǎng)膜上，有三種跨膜蛋白：IRE1、PERK (Protein kinase receptor-like ER kinase)和ATF6 (Activating transcription factor 6)[21]。三者在內(nèi)質(zhì)網(wǎng)腔內(nèi)的結(jié)構(gòu)域均與內(nèi)質(zhì)網(wǎng)分子伴侶Grp78(Glucose-regulated protein 78)結(jié)合而處于非活化狀態(tài)。內(nèi)質(zhì)網(wǎng)中的未折疊蛋白或錯(cuò)誤折疊蛋白增加時(shí)，這三種跨膜蛋白與Grp78分離而被激活。哺乳動(dòng)物有酵母Ire1的同源體IRE1α 和IRE1β，但尚未發(fā)現(xiàn)酵母Hac1的同源體。但是，哺乳動(dòng)物細(xì)胞的ATF6與酵母Hac1具有序列同源性[21]。哺乳動(dòng)物UPR的啟動(dòng)依賴于IRE1α 把XBP1u mRNA剪接為XBP1s mRNA，后者的翻譯產(chǎn)物有轉(zhuǎn)錄因子的功能；同時(shí)，還依賴于高爾基體的兩個(gè)蛋白酶S1P和S2P分步酶切ATF6，使其成為有活性的轉(zhuǎn)錄因子(圖1b和1d，表1)。ATF6激活UPR基于其結(jié)合靶基因的順式作用元件[22]。PERK可以磷酸化翻譯起始因子eIF2，導(dǎo)致細(xì)胞整體翻譯水平的下調(diào)，從而降低內(nèi)質(zhì)網(wǎng)中的蛋白負(fù)載量；同時(shí)，誘導(dǎo)轉(zhuǎn)錄因子ATF4的翻譯(圖1c，表1)。

表1 酵母細(xì)胞和哺乳動(dòng)物細(xì)胞的UPR組分比較

UPR在酵母和哺乳動(dòng)物細(xì)胞中普遍存在，并且兩者UPR激活的分子機(jī)制都存在明顯的相同點(diǎn)[25-26]。在酵母和哺乳動(dòng)物細(xì)胞中，許多條件能夠誘導(dǎo)UPR，如抑制糖基化反應(yīng)(衣霉素)、干擾二硫鍵的正常形成(DTT，β-巰基乙醇)以及破壞鈣離子體內(nèi)平衡等能夠引起內(nèi)質(zhì)網(wǎng)未折疊/錯(cuò)誤折疊蛋白積累的條件。在酵母中，這些條件激活I(lǐng)re1，從而激活HAC1 mRNA(在哺乳動(dòng)物細(xì)胞中是XBP1 mRNA)的剪切，形成有功能的轉(zhuǎn)錄因子Hac1(XBP1)。在酵母細(xì)胞中HAC1 mRNA和哺乳動(dòng)物細(xì)胞中XBP1 mRNA的剪切被認(rèn)為是內(nèi)質(zhì)網(wǎng)壓力的典型標(biāo)志。除了UPR，內(nèi)質(zhì)網(wǎng)壓力也能觸發(fā)其他反應(yīng)，尤其是鈣離子的內(nèi)流，這對(duì)細(xì)胞存活是很重要的[27]，這一過(guò)程能夠幫助蛋白質(zhì)折疊。鈣離子的內(nèi)流過(guò)程通過(guò)Slt2 MAPK途徑被激活，但不依賴于UPR[27-28]。

圖1 酵母細(xì)胞(a)和哺乳動(dòng)物細(xì)胞(b～d)中內(nèi)質(zhì)網(wǎng)應(yīng)激的感受器和UPR反應(yīng)[23-24]Fig.1 ER-stress sensors and responses in yeast and mammalian cells[23-24]

1.2 酵母細(xì)胞中UPR的類型

2 內(nèi)質(zhì)網(wǎng)應(yīng)激與有絲分裂原蛋白激酶(Mitogen-activated protein kinase, MAPK)途徑的關(guān)系

2.1 內(nèi)質(zhì)網(wǎng)應(yīng)激與高滲透壓甘油形成途徑(High Osmolarity Glycerol, HOG)的關(guān)系

當(dāng)未折疊蛋白積聚于內(nèi)質(zhì)網(wǎng)引起內(nèi)質(zhì)網(wǎng)壓力時(shí)，未折疊蛋白反應(yīng)迅速響應(yīng)誘導(dǎo)轉(zhuǎn)錄程序以緩解壓力。然而，在極端條件下，當(dāng)UPR激活不足以減輕內(nèi)質(zhì)網(wǎng)壓力時(shí)，內(nèi)質(zhì)網(wǎng)壓力可能會(huì)持續(xù)較長(zhǎng)時(shí)間。在不能通過(guò)立即激活UPR解決內(nèi)質(zhì)網(wǎng)壓力的情況下，細(xì)胞是如何反應(yīng)來(lái)抵抗內(nèi)質(zhì)網(wǎng)壓力的還不清楚。研究表明，釀酒酵母細(xì)胞中的MAP激酶-Hog1在內(nèi)質(zhì)網(wǎng)應(yīng)激階段后期被磷酸化并且?guī)椭鷥?nèi)質(zhì)網(wǎng)恢復(fù)動(dòng)態(tài)平衡[32]。在內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)后期，Hog1磷酸化移位進(jìn)入細(xì)胞核，調(diào)節(jié)基因表達(dá)。隨后，Hog1返回細(xì)胞質(zhì)，在細(xì)胞質(zhì)中其磷酸化水平仍然很高，這有助于細(xì)胞自噬的激活，其中Atg8是一個(gè)關(guān)鍵的自噬蛋白。因此，Hog1在抵抗內(nèi)質(zhì)網(wǎng)壓力上有多方面的功能。

在酵母細(xì)胞中，UPR的激活依賴于IRE1和HAC1兩個(gè)基因。內(nèi)質(zhì)網(wǎng)應(yīng)激可以誘導(dǎo)Hog1的磷酸化，但UPR的誘導(dǎo)表達(dá)并不依賴于HOG途徑。UPR通過(guò)一種特殊的機(jī)制調(diào)節(jié)Hog1的磷酸化：內(nèi)質(zhì)網(wǎng)應(yīng)激條件下，UPR可以促進(jìn)Hog1的磷酸化，Hog1的磷酸化需要IRE1和HAC1，以及HOG途徑的Ssk1支路。高滲脅迫條件下，UPR對(duì)Hog1的磷酸化沒(méi)有影響；CWI途徑條件下，UPR可以抑制Hog1的磷酸化。研究表明[32-33]，在內(nèi)質(zhì)網(wǎng)應(yīng)激條件下，HOG途徑中相關(guān)基因的缺失株表現(xiàn)出生長(zhǎng)缺陷，這說(shuō)明HOG途徑對(duì)內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)是必需的。但是，HOG途徑在內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)中的作用機(jī)制并不清楚。

2.2 內(nèi)質(zhì)網(wǎng)應(yīng)激與細(xì)胞壁完整性途徑(Cell Wall Integrity, CWI)的關(guān)系

酵母細(xì)胞壁是一種依賴于分泌蛋白和膜蛋白構(gòu)成其組分的胞外結(jié)構(gòu)，而內(nèi)質(zhì)網(wǎng)具有運(yùn)輸新合成的分泌蛋白和膜蛋白的功能。蛋白質(zhì)量控制機(jī)制在細(xì)胞壁完整性方面作用的研究表明，未折疊蛋白反應(yīng)(UPR)以及內(nèi)質(zhì)網(wǎng)相關(guān)的蛋白質(zhì)降解(Endoplasmic Reticulum-Associated Degradation, ERAD)途徑對(duì)于構(gòu)成細(xì)胞壁組分是必需的[34]。IRE1的無(wú)意突變株、ERAD組分hrd1和ubc7的雙缺失株以及ire1缺失株或錯(cuò)誤折疊蛋白的表達(dá)都與細(xì)胞壁蛋白的突變株表現(xiàn)出相似的表型，包括對(duì)破壞細(xì)胞壁化合物的高度敏感、對(duì)細(xì)胞壁蛋白層的改變、減少細(xì)胞壁的厚度以及增加細(xì)胞凝集度。與在細(xì)胞壁完整性中的重要作用一致，在細(xì)胞壁脅迫或未受脅迫生長(zhǎng)狀態(tài)下，UPR可以被細(xì)胞壁完整性途徑的MAP激酶信號(hào)途徑激活。細(xì)胞壁脅迫和本底UPR活性都受到Swi6p的調(diào)節(jié)，Swi6p是一種細(xì)胞循環(huán)和細(xì)胞壁脅迫基因轉(zhuǎn)錄的調(diào)節(jié)子，以一種不依賴于已知的共調(diào)節(jié)分子的方式進(jìn)行調(diào)節(jié)。另外，Mpk1在應(yīng)對(duì)內(nèi)質(zhì)網(wǎng)脅迫過(guò)程中被磷酸化而激活，并且在內(nèi)質(zhì)網(wǎng)脅迫條件下直接或間接激活Cch1-Mid1 Ca2+通道[28]。能引起內(nèi)質(zhì)網(wǎng)脅迫的各種試劑也會(huì)導(dǎo)致G2/M期的Swe1依賴性延遲或停止。然而，大多數(shù)細(xì)胞在任何條件下，Mpk1和鈣調(diào)磷酸酯酶對(duì)于G2/M期的延遲都不是必需的。反過(guò)來(lái)，Swe1對(duì)于CCS途徑的運(yùn)行不是必需的。在酵母中，MPK1激酶信號(hào)到達(dá)Cch1-Mid1 Ca2+通道是應(yīng)對(duì)內(nèi)質(zhì)網(wǎng)脅迫最主要的和最基本的方式[28]。

IRE1的缺失或錯(cuò)誤折疊蛋白的表達(dá)能夠?qū)е录?xì)胞對(duì)CWI途徑壓力敏感。在CWI途徑壓力作用下，UPRE-lacZ的表達(dá)活性被誘導(dǎo)，HAC1的mRNA的剪接和UPRE-lacZ的表達(dá)誘導(dǎo)依賴于Mpk1、Ire1和CWI途徑中細(xì)胞膜感受器Mid2及下游轉(zhuǎn)錄因子Swi6[34]。然而，內(nèi)質(zhì)網(wǎng)應(yīng)激條件下，Mpk1可以被磷酸化而激活但不依賴于Ire1，HAC1的mRNA的剪接也不依賴于Mpk1[35]。內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)主要是通過(guò)CWI途徑中細(xì)胞膜感受器Wsc1進(jìn)行信號(hào)傳導(dǎo)，從而激活Mpk1磷酸化。表型分析也表明，WSC1和MPK1基因的缺失可以導(dǎo)致酵母細(xì)胞對(duì)內(nèi)質(zhì)網(wǎng)應(yīng)激壓力敏感。

3 鎘離子與UPR的關(guān)系

鎘(Cd)是一種重要的重金屬環(huán)境污染物。空氣中的鎘主要來(lái)自家庭或工業(yè)產(chǎn)生的廢氣、汽車(chē)尾氣、金屬加工行業(yè)、電池或油漆制造業(yè)以及廢物的處理過(guò)程。鎘可以從污染源地隨著空氣傳播，污染食物或水質(zhì)。煙葉本身可以積累較高濃度的鎘，因而吸煙是鎘污染的重要來(lái)源之一[36]。近來(lái)的流行病學(xué)案例研究進(jìn)一步證實(shí)鎘具有致癌性。肺癌、前列腺癌、胰腺癌和腎癌的發(fā)生都與長(zhǎng)期接觸鎘有關(guān)[37-39]。鎘離子是一種毒性很強(qiáng)的金屬離子，可以在不同的細(xì)胞水平引起許多毒害作用。首先，鎘是一種能夠誘導(dǎo)細(xì)胞突變的化合物。鎘離子引起的超突變主要是通過(guò)抑制DNA修復(fù)系統(tǒng)中相關(guān)酶的活性完成的[40-41]。主要的機(jī)制有兩種，一是通過(guò)高親和力結(jié)合到蛋白活性位點(diǎn)的半胱氨酸殘基上，抑制酶的活性[41]；二是通過(guò)替換金屬蛋白酶結(jié)合的鋅離子和鈣離子抑制酶的活性[42-44]。其次，鎘可以引起氧化脅迫(ROS)。鎘能夠提高細(xì)胞內(nèi)的ROS水平從而提高脂類的過(guò)氧化作用和ROS相關(guān)的DNA損傷[45-48]。第三，鎘也可以引起酵母細(xì)胞和許多哺乳動(dòng)物細(xì)胞類型的凋亡[45,49-50]。這個(gè)過(guò)程涉及到caspase-依賴的細(xì)胞凋亡和caspase-不依賴的細(xì)胞凋亡[51-53]。最新的研究表明，對(duì)于許多細(xì)胞而言，鎘依賴的細(xì)胞凋亡是內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)應(yīng)答的結(jié)果[54-55]。到目前為止，鎘的細(xì)胞和分子生物學(xué)毒性機(jī)制尚未清楚。研究表明[56]，內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)應(yīng)答途徑中的功能基因IRE1和HAC1的缺失株對(duì)鎘耐受性是必需的，鎘能夠通過(guò)誘導(dǎo)UPR和HAC1的mRNA剪接造成釀酒酵母細(xì)胞中內(nèi)質(zhì)網(wǎng)壓力，因此在酵母細(xì)胞中內(nèi)質(zhì)網(wǎng)是鎘離子毒性的靶目標(biāo)。在哺乳動(dòng)物細(xì)胞中，鎘離子是誘導(dǎo)內(nèi)質(zhì)網(wǎng)壓力的典型標(biāo)志[54,57-58]。在腎小管細(xì)胞中，鎘離子激活哺乳動(dòng)物UPR的三個(gè)主要分支(PERK/eIF2α、IRE1/XBP1 和 ATF6 途徑)[54]；在纖維細(xì)胞中鎘離子至少能激活I(lǐng)RE1/XBP1途徑[58]。這表明在哺乳動(dòng)物細(xì)胞中，內(nèi)質(zhì)網(wǎng)可能是鎘離子毒性的靶位點(diǎn)。因此，鎘在內(nèi)質(zhì)網(wǎng)積累的結(jié)果也可以直接導(dǎo)致誘導(dǎo)內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)和鎘毒性。另外，擾亂鈣離子的內(nèi)平衡是鎘離子毒性的另一個(gè)重要方面，鎘離子不能夠抑制內(nèi)質(zhì)網(wǎng)蛋白質(zhì)二硫鍵的形成，但是能夠擾亂鈣離子代謝：鎘離子激活鈣離子通道Cch1/Mid1刺激鎘離子進(jìn)入細(xì)胞[56]。

本實(shí)驗(yàn)室最近通過(guò)對(duì)釀酒酵母非必需基因缺失株文庫(kù)基因組規(guī)模的篩選，發(fā)現(xiàn)了106個(gè)基因缺失株對(duì)鎘離子敏感，其中包括編碼兩個(gè)MAP激酶途徑——HOG途徑和CWI途徑的相關(guān)組分。進(jìn)一步研究發(fā)現(xiàn)，HOG途徑中Sho1和Sln1分支都參與了鎘脅迫下對(duì)Hog1磷酸化的激活[59]。在 CWI 途徑中，鎘激活Slt2的磷酸化是通過(guò)膜感受器Mid2p將信號(hào)通過(guò) GEFs-Rom1p傳遞到Rho1，進(jìn)而激活PKC途徑中的MAP激酶[60]。在這些研究基礎(chǔ)上，將進(jìn)一步研究鎘離子誘導(dǎo)的UPR途徑與HOG途徑和CWI途徑的關(guān)系。

4 內(nèi)質(zhì)網(wǎng)應(yīng)激與鈣離子信號(hào)途徑的關(guān)系

酵母細(xì)胞內(nèi)質(zhì)網(wǎng)鈣平衡與UPR的作用是相互的，酵母細(xì)胞中內(nèi)質(zhì)網(wǎng)中鈣的排空能夠激活依賴于Ire1和Hac1的未折疊蛋白反應(yīng)信號(hào)途徑[27]。內(nèi)質(zhì)網(wǎng)的排空刺激也可以使鈣通過(guò)細(xì)胞膜上的鈣通道Cch1-Mid1和另外一個(gè)未知系統(tǒng)(轉(zhuǎn)運(yùn)蛋白X和M)流入細(xì)胞內(nèi)。內(nèi)質(zhì)網(wǎng)上錯(cuò)誤折疊蛋白激活鈣輸入系統(tǒng)的能力是不依賴于Ire1p和Hac1p的，并且鈣的流入和信號(hào)因子也不是起始UPR信號(hào)途徑所必須的。在內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)條件下，CWI途徑中的Mpk1被磷酸化而激活[35]。而Mpk1可以直接或間接激活位于細(xì)胞膜上的鈣通道Mid1和Cch1，從而使鈣流入細(xì)胞內(nèi)。鈣通道、鈣調(diào)蛋白、鈣調(diào)磷酸酯酶和其他因子的激活是細(xì)胞應(yīng)答內(nèi)質(zhì)網(wǎng)壓力時(shí)所必需的。

哺乳動(dòng)物細(xì)胞的內(nèi)質(zhì)網(wǎng)通過(guò)內(nèi)質(zhì)網(wǎng)上高Ca2+親和力的鈣泵Ca2+-ATPase (sarco-endoplasmic reticulum Ca2+ATPase，SERCA)家族的激活積累高濃度的鈣[61-62]。這個(gè)鈣庫(kù)對(duì)蛋白質(zhì)的遷移、折疊、糖基化、二硫鍵的形成和通過(guò)內(nèi)質(zhì)網(wǎng)滯留分子伴侶來(lái)分選分泌蛋白是非常重要的[63]。引起內(nèi)質(zhì)網(wǎng)內(nèi)鈣排空的藥物，如鈣載體和螯合劑、SERCA泵的抑制劑和鈣釋放通道的激活劑等，都可以影響內(nèi)質(zhì)網(wǎng)中蛋白的折疊效率，從而激活UPR信號(hào)途徑[64]。酵母細(xì)胞缺少SERCA-型鈣泵的同源物，但是可以表達(dá)哺乳動(dòng)物分泌途徑Ca2+-ATPases(SPCAs)的同源物Pmr1[65]。Pmr1定位在高爾基體上，為高爾基復(fù)合體上高效糖基化、蛋白加工和分選反應(yīng)提供需要的鈣離子和錳離子。與用SERCA抑制劑處理的哺乳動(dòng)物細(xì)胞一樣，pmr1缺失株表現(xiàn)為通過(guò)高親和力鈣通道Cch1和Mid1高效的流入鈣，并表現(xiàn)出對(duì)內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)敏感的表型[66]。鈣離子穩(wěn)態(tài)的破壞有助于癌癥、老年癡呆癥和心血管疾病的發(fā)生和加重[67-68]。編碼人體鈣泵蛋白SERCA的基因ATP2A2突變導(dǎo)致毛囊角化病, 而ATP2A2的活性下降會(huì)妨礙鈣的吸收，這是心臟衰竭的標(biāo)志[69-70]。這些鈣離子穩(wěn)態(tài)相關(guān)的人體疾病與內(nèi)質(zhì)網(wǎng)鈣離子穩(wěn)態(tài)失衡造成的內(nèi)質(zhì)網(wǎng)應(yīng)激相關(guān)。

闡明鈣在酵母細(xì)胞內(nèi)質(zhì)網(wǎng)中的作用是非常困難的。酵母細(xì)胞的鈣結(jié)合蛋白在沒(méi)有鈣的情況下也可以發(fā)揮功能。另外，酵母細(xì)胞中內(nèi)質(zhì)網(wǎng)的鈣濃度比哺乳動(dòng)物低10～100倍[62]。缺失Pmr1的突變株積累正常內(nèi)質(zhì)網(wǎng)中一半的鈣離子，但是鈣離子濃度的降低并不能激活UPR信號(hào)途徑，這說(shuō)明酵母細(xì)胞內(nèi)質(zhì)網(wǎng)腔內(nèi)的高鈣離子濃度對(duì)蛋白質(zhì)的折疊并不是必須的[71]。由于SERCA同源物已經(jīng)在動(dòng)物、植物、無(wú)脊椎動(dòng)物以及其他真菌中發(fā)現(xiàn)[72]，在芽殖酵母進(jìn)化過(guò)程中SERCA-樣酶的缺失反應(yīng)了鈣離子在內(nèi)質(zhì)網(wǎng)折疊反應(yīng)中作用的降低。另外，其他鈣離子-ATPases，例如Pmr1p、Pmc1p或者新發(fā)現(xiàn)的P型-ATPase Cod1/Spf1[73]，都補(bǔ)償了酵母細(xì)胞中原有SERCA的缺失。文獻(xiàn)報(bào)道[27]，內(nèi)質(zhì)網(wǎng)中蛋白質(zhì)折疊或者麥角固醇合成的抑制劑都會(huì)刺激鈣離子的流入(通過(guò)Cch1-Mid1鈣通道和其他途徑)和/或激活細(xì)胞存活所必須的鈣信號(hào)途徑。這種鈣離子細(xì)胞存活途徑在其他治病酵母菌——白色念珠菌和光滑假絲酵母菌中可以被激活[74]。

前期工作中，通過(guò)基因組規(guī)模的遺傳學(xué)篩選，我們發(fā)現(xiàn)120個(gè)基因的缺失導(dǎo)致釀酒酵母細(xì)胞對(duì)鈣敏感[75]，包括7個(gè)ESCRT基因(SNF7、SNF8、VPS20、STP22、VPS25、VPS28和VPS36)的缺失株。內(nèi)質(zhì)網(wǎng)/高爾基體膜上的鈣泵Pmr1是維持內(nèi)質(zhì)網(wǎng)鈣濃度所必須的，PMR1的缺失可以導(dǎo)致對(duì)內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)敏感。我們進(jìn)一步發(fā)現(xiàn)，7個(gè)ESCRT基因通過(guò)Rim101/ Nrg1這條負(fù)向調(diào)控信號(hào)途徑來(lái)調(diào)控PMR1的表達(dá)(圖2)[76]。在上述研究的基礎(chǔ)上，對(duì)以前我們發(fā)現(xiàn)的120個(gè)鈣敏感基因缺失株進(jìn)行內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)敏感篩選，找出對(duì)鈣和內(nèi)質(zhì)網(wǎng)應(yīng)激壓力均敏感的基因缺失株，進(jìn)而研究鈣在內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)應(yīng)答過(guò)程中的作用。

圖2 PMR1的正調(diào)控和負(fù)調(diào)控Fig.2 Positive and negative regulation of PMR1 gene

5 結(jié)論與展望

除了作為蛋白質(zhì)合成、折疊和翻譯后修飾的部位，內(nèi)質(zhì)網(wǎng)還是細(xì)胞內(nèi)鈣主要的存儲(chǔ)位置，并通過(guò)多個(gè)集成系統(tǒng)維持鈣離子穩(wěn)態(tài)。內(nèi)質(zhì)網(wǎng)內(nèi)的鈣離子由鈣泵蛋白SERCA從胞質(zhì)內(nèi)攝入，降低SERCA表達(dá)會(huì)導(dǎo)致內(nèi)質(zhì)網(wǎng)內(nèi)的鈣離子儲(chǔ)存耗竭和內(nèi)質(zhì)網(wǎng)應(yīng)激相關(guān)的細(xì)胞凋亡，而SERCA的過(guò)度表達(dá)則可以減輕內(nèi)質(zhì)網(wǎng)應(yīng)激程度。因此，內(nèi)質(zhì)網(wǎng)內(nèi)的鈣離子穩(wěn)態(tài)直接與內(nèi)質(zhì)網(wǎng)應(yīng)激相關(guān)。闡明內(nèi)質(zhì)網(wǎng)應(yīng)激過(guò)程的功能和調(diào)控機(jī)制對(duì)進(jìn)一步了解以上人體相關(guān)疾病的發(fā)生機(jī)理有十分重要的理論意義。釀酒酵母作為一種模式生物，被廣泛用于科學(xué)研究。因此，研究釀酒酵母細(xì)胞內(nèi)的UPR應(yīng)答機(jī)制將為了解哺乳動(dòng)物細(xì)胞的相關(guān)機(jī)制提供重要線索。

鎘可以誘導(dǎo)酵母和動(dòng)物細(xì)胞凋亡，而鎘誘導(dǎo)的細(xì)胞凋亡是內(nèi)質(zhì)網(wǎng)應(yīng)激的結(jié)果，內(nèi)質(zhì)網(wǎng)是鎘的靶細(xì)胞器。目前，鎘的細(xì)胞毒性作用已有很多報(bào)道，但其作用靶點(diǎn)及毒性機(jī)理并不十分明確。鎘可以影響DNA復(fù)制和修復(fù)、細(xì)胞周期進(jìn)程、生長(zhǎng)和分化以及凋亡。鎘能干擾細(xì)胞生長(zhǎng)所必需的鈣、鋅、鐵等離子的穩(wěn)態(tài)。雖然鎘本身沒(méi)有氧化還原活性，不能與DNA直接作用，但它可以間接誘導(dǎo)氧化脅迫，破壞基因組的完整性。而細(xì)胞內(nèi)的氧化脅迫是誘導(dǎo)內(nèi)質(zhì)網(wǎng)應(yīng)激的因素之一。鎘可以激活兩個(gè)MAPK激酶Hog1和Slt2的磷酸化，而這兩個(gè)MAPK與細(xì)胞內(nèi)的各種應(yīng)激反應(yīng)是密切相關(guān)的。因此鎘和內(nèi)質(zhì)網(wǎng)應(yīng)激的關(guān)系值得深入研究。

[1]Xu C,Bailly-Maitre B,Reed JC.Endoplasmic reticulum stress:cell life and death decisions[J].Journal of Clinical Investigation,2005,115(10):2656-2664.

[2]Cao SS,Kaufman RJ.Endoplasmic reticulum rtress and oxidativestress in cell fate decision and human disease[J].Antioxidants and Redox Signaling,2014,21(3):396-413.

[3]He B.Viruses,endoplasmic reticulum stress,and interferon responses[J].Cell Death and Differentiation,2006,13(3):393-403.

[4]Han J,Back SH,Hur J.ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death[J].Nature Cell Biology,2013,15(5):481-490.

[5]Malhotra JD,Miao H,Zhang K.Antioxidants reduce endoplasmic reticulum stress and improve protein secretion[J].Proceedings of the National Academy of Sciences of the United States of America,2008,105(47):18525-18530.

[6]Mekahli D,Bultynck G,Parys JB,et al.Endoplasmic reticulum calcium depletion and disease[J].Cold Spring Harbor Perspectives in Biology,2011,3(6).pii:a004317.doi:10.1101/cshperspect.a004317.

[7]Wang S,Kaufman RJ.The impact of the unfolded protein response on human disease[J].Journal of Cell Biology,2012,197(7):857-867.

[8]Yoshida H.ER stress and diseases[J].Febs Journal,2007,274(3):630-658.

[9]Oyadomari S,Araki E,Mori M.Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells[J].Apoptosis,2002,7(4):335-345.

[10]Liang CP,Han S,Li G,et al.Impaired MEK signaling and SERCA expression promote ER stress and apoptosis in insulin-resistant macrophages and are reversed by exenatide treatment[J].Diabetes, 2012,61(10):2609-2620.

[11]Cui J,Kaandorp JA,Sloot PM,et al.Calcium homeostasis and signaling in yeast cells and cardiac myocytes[J].FEMS Yeast Research,2009,9(8):1137-1147.

[12]Kozutsumi Y,Segal M,Normington K,et al.The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins[J].Nature,1988,332(6163):462-464.

[13]Sidrauski C,Chapman R,WALTER P.The unfolded protein response:an intracellular signalling pathway with many surprising features[J].Trends in Cell Biology,1998,8(6):245-249.

[14]Ron D,Walter P.Signal integration in the endoplasmic reticulum unfolded protein response[J].Nature Reviews Molecular Cell Biology,2007,8(7):519-529.

[15]Ma Y,Hendershot LM.The unfolding tale of the unfolded protein response[J].Cell,2001,107(7):827-830.

[16]Kimata Y,Ishiwata-Kimata Y,Ito T,et al.Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins[J].Journal of Cell Biology,2007,179(1):75-86.

[17]Aragon T,van Anken E,Pincus D,et al.Messenger RNA targeting to endoplasmic reticulum stress signalling sites[J].Nature,2009,457(7230):736-740.

[18]Mori K,Ogawa N,Kawahara T,et al.Palindrome with spacer of one nucleotide is characteristic of the cis-acting unfolded protein response element inSaccharomycescerevisiae[J].The Journal of Biological Chemestry,1998,273(16):9912-9920.

[19]Hu Z,Killion PJ,Iyer VR.Genetic reconstruction of a functional transcriptional regulatory network[J].Nature Genetics,2007,39(5):683-687.

[20]MacIsaac KD,Wang T,Gordon DB,et al.An improved map of conserved regulatory sites forSaccharomycescerevisiae[J].BMC Bioinformatics,2006,7:113.

[21]Ye J,Rawson RB,Komuro R,et al.ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs[J].Molecular Cell,2000,6(6):1355-1364.

[22]Lee K,Tirasophon W,Shen X,et al.IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response[J].Genes & Development,2002,16(4):452-466.

[23]Kimata Y, Kohno K. Endoplasmic reticulum stress-sensing mechanisms in yeast and mammalian cells[J].Current Opinion in Cell Biology,2011,23(2):135-142.

[24]Boyce M,Yuan J.Cellular response to endoplasmic reticulum stress: a matter of life or death[J].Cell Death and Differentiation,2006,13(3):363-373.

[25]Bernales S,Papa FR,Walter P.Intracellular signaling by the unfolded protein response[J].Annual Review of Cell and Developmental Biology,2006,22:487-508.

[26]Zhang K, Kaufman RJ. The unfolded protein response: a stress signaling pathway critical for health and disease[J]. Neurology, 2006, 66 (2 Suppl 1): S102-109.

[27]Bonilla M, Nastase KK, Cunningham KW. Essential role of calcineurin in response to endoplasmic reticulum stress[J]. EMBO Journal, 2002, 21(10): 2343-2353.

[28]Bonilla M, Cunningham KW. Mitogen-activated protein kinase stimulation of Ca2+signaling is required for survival of endoplasmic reticulum stress in yeast[J]. Molecular and Cellular Biology, 2003, 14(10): 4296-4305.

[29]Mori K, Ogawa N, Kawahara T, et al. Palindrome with spacer of one nucleotide is characteristic of the cis-acting unfolded protein response element inSaccharomycescerevisiae[J]. The Journal of Biological Chemistry, 1998, 273(16): 9912-9920.

[30]Carrara M, Prischi F, Nowak PR, et al. Crystal structures reveal transient PERK luminal domain tetramerization in endoplasmic reticulum stress signaling[J]. EMBO Journal, 2015, 34(11):1589-1600.

[32]Bicknell AA, Tourtellotte J, Niwa M. Late phase of the endoplasmic reticulum stress response pathway is regulated by Hog1 MAP kinase[J]. The Journal of Biological Chemistry, 2010, 285(23): 17545-17555.

[33]Torres-Quiroz F, Garcia-Marques S, Coria R, et al. The activity of yeast Hog1 MAPK is required during endoplasmic reticulum stress induced by tunicamycin exposure[J]. The Journal of Biological Chemistry, 2010, 285(26): 20088-20096.

[34]Scrimale T, Didone L, de Mesy Bentley KL, et al. The unfolded protein response is induced by the cell wall integrity mitogen-activated protein kinase signaling cascade and is required for cell wall integrity inSaccharomycescerevisiae[J]. Molecular and Cellular Biology, 2009, 20(1): 164-175.

[35]Babour A, Bicknell AA, Tourtellotte J, et al. A surveillance pathway monitors the fitness of the endoplasmic reticulum to control its inheritance[J]. Cell, 2010, 142(2): 256-269.

[36]Ashraf MW. Concentrations of cadmium and lead in different cigarette brands and human exposure to these metals via smoking[J]. Journal of Arts, Science & Commerce, 2011, 2: 140-147.

[37]Nawrot T, Plusquin M, Hogervorst J, et al. Environmental exposure to cadmium and risk of cancer: a prospective population-based study[J]. The Lancet Oncology, 2006, 7(2): 119-126.

[38]Kellen E, Zeegers MP, Hond ED, et al. Blood cadmium may be associated with bladder carcinogenesis: the Belgian case-control study on bladder cancer[J]. Cancer Detection and Prevention, 2007, 31(1): 77-82.

[39]Gallagher CM, Chen JJ, Kovach JS. Environmental cadmium and breast cancer risk[J]. Aging (Albany NY), 2010, 2(11): 804-814.

[40]Jin YH, Clark AB, Slebos RJC, et al. Cadmium is a mutagen that acts by inhibiting mismatch repair[J]. Nature Genetics, 2003, 34(3): 326-329.

[41]Bravard A, Vacher M, Gouget B, et al. Redox regulation of human OGG1 activity in response to cellular oxidative stress[J]. Molecular and Cellular Biology, 2006, 26: 7430-7436.

[42]Stohs SJ, Bagchi D. Oxidative mechanisms in the toxicity of metal ions[J]. Free Radical Biology and Medicine, 1995, 18(2): 321-336.

[43]Schutzendubel A, Polle A. Plant responses to abiotic stresses: heavy metal-induced oxidative stress and protection by mycorrhization[J]. Journal of Experimental Botany, 2002, 53(372): 1351-1365.

[44]Faller P, Kienzler K, Krieger-Liszkay A. Mechanism of Cd2+toxicity: Cd2+inhibits photoactivation of Photosystem II by competitive binding to the essential Ca2+site[J]. Biochimica et Biophysica Acta, 2005, 1706(1-2): 158-164.

[45]Pulido MD, Parrish AR. Metal-induced apoptosis: mechanisms[J]. Mutatation Reserach, 2003, 533(1-2): 227-241.

[46]Howlett NG, Avery SV. Induction of lipid peroxidation during heavy metal stress inSaccharomycescerevisiaeand influence of plasma membrane fatty acid unsaturation[J]. Applied and Environmental Microbiology, 1997, 63(8): 2971-2976.

[47]Ercal N, Gurer-Orhan H, Aykin-Burns N. Toxic metals and oxidative stress part I: mechanisms involved in metal-induced oxidative damage[J]. Current Topics in Medicinal Chemistry, 2001, 1(6): 529-539.

[48]Lopez E, Arce C, Oset-Gasque MJ, et al. Cadmium induces reactive oxygen species generation and lipid peroxidation in cortical neurons in culture[J]. Free Radical Biology and Medicine, 2006, 40(6): 940-951.

[49]Nargund AM, Avery SV, Houghton JE. Cadmium induces a heterogeneous and caspase-dependent apoptotic response inSaccharomycescerevisiae[J]. Apoptosis, 2008, 13(6): 811-821.

[50]Bertin G, Averbeck D. Cadmium: cellular effects, modifications of biomolecules, modulation of DNA repair and genotoxic consequences (a review)[J]. Biochimie, 2006, 88(11): 1549-1559.

[51]Li M, Kondo T, Zhao Q L, et al. Apoptosis induced by cadmium in human lymphoma U937 cells through Ca2+-calpain and caspase-mitochondria-dependent pathways[J]. The Journal of Biological Chemistry, 2000, 275(50): 39702-39709.

[52]Lemarie A, Lagadic-Gossmann D, Morzadec C, et al. Cadmium induces caspase-independent apoptosis in liver Hep3B cells: role for calcium in signaling oxidative stress-related impairment of mitochondria and relocation of endonuclease G and apoptosis-inducing factor[J]. Free Radical Biology and Medicine, 2004, 36(12): 1517-1531.

[53]Coutant A, Lebeau J, Bidon-Wagner N, et al. Cadmium-induced apoptosis in lymphoblastoid cell line: involvement of caspase-dependent and-independent pathways[J]. Biochimie, 2006, 88(11): 1815-1822.

[54]Yokouchi M, Hiramatsu N, Hayakawa K, et al. Atypical, bidirectional regulation of cadmium-induced apoptosis via distinct signaling of unfolded protein response[J]. Cell Death and Differentiation, 2007, 14(8): 1467-1474.

[55]Yokouchi M, Hiramatsu N, Hayakawa K, et al. Involvement of selective reactive oxygen species upstream of proapoptotic branches of unfolded protein response[J]. The Journal of Biological Chemistry, 2008, 283(7): 4252-4260.

[56]Gardarin A, chedin S, lagniel G, et al. Endoplasmic reticulum is a major target of cadmium toxicity in yeast[J]. Molecular Microbiology, 2010, 76(4): 1034-1048.

[57]Liu F, Inageda K, Nishitai G, et al. Cadmium induces the expression of Grp78, an endoplasmic reticulum molecular chaperone, in LLC-PK1 renal epithelial cells[J]. Environmental Health Perspectives, 2006, 114(6): 859-864.

[58]Biagioli M, Pifferi S, Ragghianti M, et al. Endoplasmic reticulum stress and alteration in calcium homeostasis are involved in cadmium-induced apoptosis[J]. Cell Calcium, 2008, 43(2): 184-195.

[59]Jiang L, Cao C, Zhang L, et al. Cadmium-induced activation of high osmolarity glycerol pathway through its Sln1 branch is dependent on the MAP kinase kinase kinase Ssk2, but not its paralog Ssk22, in budding yeast[J]. FEMS Yeast Research, 2014, 14(8): 1263-1272.

[60]Xiong B, Zhang L, Xu H, et al. Cadmium induces the activation of cell wall integrity pathway in budding yeast[J]. Chemico Biological Interacttions, 2015, 240: 316-323.

[62]Tadic V, Prell T, Lautenschlaeger J, et al. The ER mitochondria calcium cycle and ER stress response as therapeutic targets in amyotrophic lateral sclerosis[J]. Frontiers in Cellular Neuroscience, 2014, 8:147.

[63]Nurbaeva MK, Eckstein M, Snead ML, et al. Store-operated Ca2+entry modulates the expression of enamel genes[J]. Journal of Dental Research, 2015, 94(10):1471-1477.

[64]Azzimonti B, Dell'oste V, Borgogna C, et al. The epithelial-mesenchymal transition induced by keratinocyte growth conditions is overcome by E6 and E7 from HPV16, but not HPV8 and HPV38: characterization of global transcription profiles[J]. Virology, 2009, 388(2):260-269.

[65]Strayle J, Pozzan T, Rudolph HK. Steady-state free Ca2+in the yeast endoplasmic reticulum reaches only 10 microM and is mainly controlled by the secretory pathway pump Pmr1[J]. EMBO Journal, 1999, 18(17): 4733-4743.

[66]Locke EG, Bonilla M, Liang L, et al. A homolog of voltage-gated Ca2+channels stimulated by depletion of secretory Ca2+in yeast[J]. Molecular and Cellular Biology, 2000, 20(18): 6686-6694.

[67]Camandola S, Mattson MP. Aberrant subcellular neuronal calcium regulation in aging and Alzheimer's disease[J]. Biochimica et Biophysica Acta, 2011, 1813(5): 965-973.

[68]Varghese J, Rich T, Jimenez C. Benign familial hypocalciuric hypercalcemia[J]. Endocrine Practice, 2011,Suppl 1, 13-17.

[69]Huo J, Liu Y, Ma J, et al. A novel splice-site mutation of ATP2A2 gene in a Chinese family with Darier disease[J]. Archives Dermatological Research, 2010, 302(10): 769-772.

[70]Kho C, Lee A, Jeong D, et al. SUMO1-dependent modulation of SERCA2a in heart failure[J]. Nature, 2011, 477(7366): 601-605.

[71]Devasahayam G, Burke DJ, Sturgill TW. Golgi manganese transport is required for rapamycin signaling inSaccharomycescerevisiae[J]. Genetics, 2007, 177(1):231-238.

[72]Cyert MS, Philpott CC. Regulation of cation balance inSaccharomycescerevisiae[J]. Genetics, 2013 , 193(3):677-713.

[73]Cronin SR, Khoury A, Ferry DK, et al. Regulation of HMG-CoA reductase degradation requires the P-type ATPase Cod1p/Spf1p[J]. Journal of Cell Biology, 2000, 148(5): 915-924.

[74]Brand A, Lee K, Veses V, et al. Calcium homeostasis is required for contact-dependent helical and sinusoidal tip growth in Candida albicans hyphae[J]. Molecular Microbiology, 2009,71(5):1155-1164.

[75]Zhao Y, Du J, Zhao G, et al. Activation of calcineurin is mainly responsible for the calcium sensitivity of gene deletion mutations in the genome of budding yeast[J]. Genomics, 2013, 101(1): 49-56.

[76]Zhao Y, Du J, Xiong B, et al. ESCRT components regulate the expression of the ER/Golgi calcium pump genePMR1 through the Rim101/Nrg1 pathway in budding yeast[J]. Journal of Molecular Cell Biology, 2013, 5(5): 336-344.

Advances in Endoplasmic Reticulum Stress and Unfolded Protein Response inSaccharomycescerevisiae

ZHAO Yun-ying, WANG Di, YUAN Fan, JIANG Ling-huo

(TheNat’lEngin.Lab.forCerealFerment’nTechnol.,Schl.ofBiotech.,JiangnanUni.,Wuxi214122)

Unfolded protein response (UPR) signaling pathway activated by endoplasmic reticulum stress is highly conserved in bothSaccharomycescerevisiaeand mammalian cells. Reticulum Endoplasmic (ER) is an organelle for protein synthesis, folding and modification as well as one of the main places for storage Ca2+.The homeostasis of Ca2+and UPR are interrelated and interact on each other. The two MAPK pathways, HOG pathway and CWI pathway are all necessary for cell survival under ER stress treated conditions. And ion of heavy metal cadmium is also able to activate the UPR pathway and it enters into the cells through activating the calcium channel Cch1/Mid1 to affect the function of calcium ion. The interactions between two MAPK kinase pathways, cadmium or calcium ion homeostasis and UPR signaling activated by endoplasmic reticulum stress inS.cerevisiaecells are all summarized in this review.

unfolded protein response; endoplasmic reticulum stress; MAPK; calcium signaling pathway;Saccharomycescerevisiae

國(guó)家自然科學(xué)基金項(xiàng)目(81371784，31301021)；中國(guó)博士后科學(xué)基金第55批資助項(xiàng)目(5924130201140280)

趙運(yùn)英 女，講師。從事酵母遺傳學(xué)和分子生物學(xué)研究工作。E-mail：yunying1213@hotmail.com

* 通訊作者。男，教授，博士生導(dǎo)師。從事酵母和絲狀真菌遺傳學(xué)與分子生物學(xué)研究工作。E-mail：linghuojiang@jiangnan.edu.cn

2016-03-25；

2016-08-31

Q93

A

1005-7021(2017)02-0098-09

10.3969/j.issn.1005-7021.2017.02.017