全 文 ：植物生理学报 Plant Physiology Journal 2015, 51 (2): 159~165　　doi: 10.13592/j.cnki.ppj.2014.0540 159
收稿 2014-11-27　　修定 2015-02-05
资助 国家自然科学基金(30600203)和河南农业大学特聘教授启
动经费(30500235)。
* 通讯作者(E-mail: zhhairong@hotmail.com; Tel: 0371-
55070851)。
植物蛋白质翻译水平的调控
李厚华, 孔伟胜, 魏圆圆, 张海荣*
河南农业大学生命科学学院, 郑州450002
摘要: 不同的逆境条件可引起生物机体不同的应答反应, 其中PKR (protein kinase double-stranded RNA-dependent)、PERK
(PKR-like endoplasmic reticulum kinase)、HRI (heme-regulated inhibitor)和GCN2 (general control non-derepressible-2)激活后使
真核蛋白翻译起始因子2 (eIF2)磷酸化, 抑制蛋白质的翻译起始, 帮助生物体适应各种逆境条件。雷帕霉素的靶蛋白(TOR)是
一个进化上相对保守的丝氨酸/苏氨酸激酶, 参与细胞生长与增殖、新陈代谢以及蛋白质的翻译等进程, 对细胞的正常生长
发育有重要作用。近几年的研究表明, eIF2和TOR介导的信号途径在植物中是保守的, 共同参与了蛋白翻译水平的调控。本
文综述了植物中eIF2和TOR介导的信号途径对蛋白翻译过程的调控机制, 以及蛋白质翻译在植物响应逆境中的重要作用。
关键词: GCN2; eIF2; TOR; 蛋白翻译
Regulation of Protein Translation Level in Plants
LI Hou-Hua, KONG Wei-Sheng, WEI Yuan-Yuan, ZHANG Hai-Rong*
College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China
Abstract: There are different responses in organisms to different stress conditions. Under different stress, acti-
vated protein kinase double-stranded RNA-dependent (PKR), PKR-like endoplasmic reticulum kinase (PERK),
heme-regulated inhibitor (HRI) and general control non-derepressible-2 (GCN2) mediate the phosphorylation
of α subunit of eukaryotic translation initiation factor 2 (eIF2), which inhibits the initiation of protein transla-
tion. As a serine/threonine kinase, target of rapamycin (TOR) plays an important role in cell growth and prolif-
eration, metabolism and protein translation. In recent years, hundreds of studies have explored that eIF2 and
TOR signals are conservatively involved in the regulation of protein translation in plants. In the review, we
summarize the regulatory mechanisms of eIF2 and TOR signaling and emphasize the importance of protein
translation in response to stresses in plants.
Key words: GCN2; eIF2; TOR; protein translation
蛋白质是生命体重要的组成部分, 是维持生
物机体生长发育的基础。生物在逆境条件下, 蛋
白质的合成受到影响, 进而打破生物体内的正常
代谢平衡, 影响生物细胞的正常生长, 严重时会导
致细胞死亡。生物体对于外界的不利条件, 自身
存在抵抗和缓解外界胁迫的机制, 其中一些机制
是通过调节体内蛋白质合成的关闭和开启来实现
的。真核翻译起始因子(eukaryotic translation initiation
factor 2, eIF2)控制体内蛋白翻译的起始, 由α、β、
γ三个亚基组成。其中 , α亚基可以被激酶PKR
(protein kinase double-stranded RNA-dependent)、
PERK (PKR-like endoplasmic reticulum kinase)、
HRI (heme-regulated inhibitor)和GCN2 (general
control non-derepressible-2)磷酸化(Donnelly等
2013)。磷酸化的eIF2与GDP和eIF2B结合形成
P-eIF2-GDP-eIF2B稳定结构, eIF2B不能将其转换
为eIF2-GTP起始翻译(Kaufman等2002)。由于
eIF2B含量较少, 只有eIF2的1/10左右(Jennings等
2013), eIF2磷酸化后占据了绝大多数的eIF2B, 导
致蛋白质的合成受到抑制。同时, eIF2α磷酸化使
体内TC (eIF2-GTP-aminoacyl- tRNAiMet/ternary
complex)含量减少, 促进GCN4的翻译, 使分子伴
侣、氨基酸合成等相关基因的表达起始(Hinnebus-
ch 2005; Hinnebusch和Lorsch 2012), 帮助生物体适
应逆境胁迫。
雷帕霉素的靶蛋白(target of rapamycin, TOR)
是一个进化上保守的丝氨酸/苏氨酸激酶, 普遍存
植物生理学报160
在于哺乳动物、酵母细胞以及植物中。TOR通过
磷酸化S6K1 (40S ribosomal protein S6 kinase 1)和
4E-BP1 (4E-binding protein 1)参与蛋白翻译的起始,
TOR也参与细胞的生长、增殖、细胞自噬、新陈
代谢等过程(Broach 2012; Laplante和Sabatini 2009;
Xiong和Sheen 2014), 对细胞正常的生长发育有重
要的作用。
本文基于近几年的研究结果, 讨论了植物中
GCN2-eIF2途径和TOR途径与蛋白翻译之间的关系。
1 eIF2途径
1.1 eIF2控制的蛋白质翻译水平的调控
在真核生物中, 翻译起始因子eIF2控制体内
蛋白翻译的起始。当机体受到某些胁迫时, eIF2的
α亚基被磷酸化, 从而抑制体内蛋白质的合成。在
正常情况下, 活化状态下的eIF2-GTP与甲硫氨酰
tRNA结合, 形成TC复合体后, 再与核糖体的40S小
亚基结合, 开始阅读mRNA (Hinnebusch 2005); 读
到起始密码子AUG时, eIF5水解GTP, 释放eIF2-
GDP, 并招募核糖体60S亚基与40S亚基形成完整
的核糖体(Jennings等2013), 开始蛋白质的翻译。
释放后的eIF2-GDP与eIF2B结合, eIF2B具有GEF
(guanine nucleotide exchange factor)的功能, 把eIF2-
GDP转换成为eIF2-GTP进入下一个循环。当机体
受到胁迫时, eIF2的激酶将其α亚基的第51位氨基
酸丝氨酸磷酸化, 被磷酸化的eIF2-GDP与eIF2B结
合后, 稳定地以P-eIF2-GDP-eIF2B的形式存在,
eIF2B不能将其转换为eIF2-GTP (Jennings等2013)。
由于eIF2B含量较少, eIF2B与磷酸化的eIF2-GDP
结合后, 体内游离的eIF2B含量降低, 抑制蛋白质
的合成; 另一方面, eIF2-GTP含量降低导致TC复合
体减少, 诱导GCN4的合成(Hinnebusch 2005; Hin-
nebusch和Lorsch 2012), 帮助机体适应并度过逆境
环境。
1.2 eIF2激酶
eIF2由α、β、γ三个亚基组成, 其中α可以被
激酶PKR、PERK、HRI和GCN2磷酸化, 这4种激
酶分别响应不同的胁迫, 被激活后磷酸化eIF2α, 抑
制体内蛋白翻译(图1) (Donnelly等2013)。PKR蛋
白定位在细胞质以及细胞核中, N端含有一个ds-
RBD (double-stranded RNA binding domain)区, 可
以与RNA结合, C端是一个KD (kinase domain)区,
能响应病毒感染以及内质网胁迫(endoplasmic retic-
ulum stress) (Chakrabarti等2011)。当内质网中存在
错误折叠蛋白并引起内质网胁迫时, 位于内质网腔
中的PERK蛋白的N端与BiP (heavy-chain binding
protein)蛋白解离, 在细胞质中含有激酶区的C端发
图1 eIF2响应逆境信号途径
Fig.1 eIF2 signaling pathways in response to stersses
uORF: up open reading frame。
李厚华等: 植物蛋白质翻译水平的调控 161
生自身磷酸化, PERK途径被激活(Chakrabarti等
2011)。HRI的N端与血红素结合, 响应体内血红素
缺乏引起的胁迫(Rafie-Kolpin等2000)。氨基酸缺
乏导致体内空载tRNA的含量升高, 当有空载tRNA
进入核糖体的A位参与蛋白翻译时, 就会被发现并
结合到GCN2的HisRS-like结构域(histidyl-tRNA
synthetases like domain), 激活GCN2 (Castilho等
2014)。PKR、PERK、HRI和GCN2四种激酶在哺
乳动物中都存在(Donnelly等2013), 在酵母细胞中
只发现有GCN2 (Narasimhan等2004), 目前拟南芥
中发现的eIF2α激酶也只有GCN2一种(Li等2013;
Zhang等2003, 2008)。
1.3 GCN2激酶的激活以及调控机制
酵母细胞中的GCN2有多个结构域, 共同调控
GCN2的激活。其中, GCN1可以与GCN2的RWD
(RING finger proteins, WD-repeat-containing proteins,
and yeast DEAD-like helicases)结构域结合, 促进
GCN2的激活(Sattlegger和Hinnebusch 2000); YKD
(pseudokinase domain)可变构调节KD (kinase do-
main), 让隐藏的激酶区暴露出来, 调节GCN2的活
性(Lageix等2014); KD是GCN2的激酶结构域, 可磷
酸化eIF2的α亚基; HisRS-like结构域能与空载tRNA
结合, 进而改变GCN2的构象, 激活GCN2 (Castilho
等2014; Hinnebusch 2005)。
在酵母细胞中 , 氨基酸缺乏时 , 胞内空载
tRNA含量增加。当有空载tRNA被运送到核糖体
的A位时, 就会被检测并与GCN2的HisRS-like结构
域结合, 使GCN2二聚化并自身磷酸化, 改变构象,
暴露激酶位点, 磷酸化eIF2的α亚基, 抑制蛋白合
成, 同时诱导GCN4的合成(Hinnebusch 2005; Lageix
等2014; Narasimhan等2004)。在这个过程中, GCN1
与GCN20以复合体的形式存在, 促进GCN2的激
活。GCN20是一个ABC (ATP-binding cassette)家族
的蛋白, 其与GCN1都有一个eEF3 (eukaryotic trans-
lation elongation factor 3)类似区域, 而且GCN20的
N端与GCN1的eEF3类似区域结合(Marton等1993;
Vazquez de Aldana等1995); 在gcn1突变体中, 氨基
酸缺乏不能激活GCN2, 说明GCN1/GCN20复合体
可能有支架蛋白和/或运送tRNA的功能, 通过转运
空载tRNA促进GCN2的激活(Marton等1993; Sat-
tlegger和Hinnebusch 2000)。
除氨基酸缺乏外 , 还有多种胁迫都可激活
GCN2并磷酸化eIF2α, 包括紫外照射(Grallert和Boye
2007)、葡萄糖缺乏(Yang等2000; Ye等2010)、病
毒侵染(Berlanga等2006)、细胞内酸化(Hueso等
2012)、雷帕霉素处理(Cherkasova和Hinnebusch
2003)等。
在植物中, eIF2α的激酶只发现GCN2一种。
拟南芥中GCN2的同源基因AtGCN2 (Arabidopsis
thaliana GCN2)也响应氨基酸缺乏, 与空载tRNA结
合, 磷酸化eIF2α (Li等2013; Zhang等2003, 2008),
并抑制体内蛋白质的合成(Lageix等2008)。除氨基
酸缺乏外, 还有多种胁迫可以激活AtGCN2磷酸化
eIF2α, 包括紫外照射、伤害处理、冷胁迫、水杨
酸处理、重金属镉中毒、除草剂处理(Lageix等
2008; Sormani等2011; Zhang等2008)等。
酵母细胞中YIH1 (yeast impact homologue)和
Gir2 (genetically interacts with ribosomal genes 2)蛋
白有一个与GCN2类似的RWD区, 可与GCN1结合,
竞争性抑制GCN2的激活(Ishikawa等2013; Sattlegger
等2011; Wout等2009)。哺乳动物中YIH1的同源蛋
白IMPACT (imprinted gene with ancient domain)同
样也能与GCN1结合, 竞争性抑制GCN2 (Cambiaghi
等2014)。在植物中并没有发现可以和GCN1结合,
竞争性抑制GCN2的蛋白。在拟南芥中AtGCN1参
与植物的免疫响应(Monaghan和Li 2010); 而Luna
等(2014)报道, BABA (β-aminobutyric acid)激活
AtGCN2磷酸化eIF2α, 缓解BABA引起的植物生长
抑制, 但与BABA引起的植物免疫无关。植物中
GCN1是否参与GCN2的激活还有待进一步证实。
2 TOR信号途径
TOR途径最早发现于酵母细胞中(Heitman等
1991), 在酵母细胞中TOR参与细胞生长、蛋白翻
译、细胞自噬等过程; 酵母中2种TOR蛋白: TOR1
和TOR2, 分别组成TOR复合体1 (TOR complex 1,
TORC1)和TOR复合体2 (TOR complex 2, TORC2),
其中雷帕霉素可以抑制TO R C 1的活性 , 但对
TORC2并没有抑制作用(Barbet等1996; Hughes
Hallett等2014; Inoki等2005; Loewith等2002; Vla-
hakis等2014; Zheng等1995)。
哺乳动物中, 只有1种mTOR (mammalian TOR)
蛋白, 但mTOR可以分别与不同的蛋白组成2种复合
植物生理学报162
体: mTORC1和mTORC2。雷帕霉素通过FKBP12
(FK506-binding protein of 12 kDa)与mTORC1的FRB
(FKBP rapamycin binding)区域结合, 抑制mTORC1
的激活; 而在mTORC2中含有一个Rictor (rapamycin-
insensitive companion of mTOR)蛋白亚基, 所以, 雷
帕霉素并不能抑制mTORC2的活性(Laplante和
Sabatini 2009)。在哺乳动物中, mTORC1通过磷酸
化S6K1和4E-BP1参与蛋白翻译起始的调控(Ma和
Blenis 2009; Thoreen等2012) (图2)。
于植物中tor纯合突变是致死的(Xiong和Sheen
2012), 导致植物中TOR信号途径的研究非常滞
后。酵母双杂交的结果证明, 在雷帕霉素存在的
情况下, AtTOR (Arabidopsis thaliana TOR)可与酵
母及哺乳动物中的FKBP12结合, 但不能与拟南芥
中的FKBP12结合; 在转入酵母FKBP12 (ScFKBP12)
蛋白的拟南芥转基因植株中 , 雷帕霉素能抑制
AtTOR的活性, 抑制植物生长, 暗示可能是由于拟
南芥中FKBP12构象的改变导致雷帕霉素不能与
AtTOR结合, 从而抑制植物生长(Mahfouz等2006;
Menand等2002; Sormani等2007; Zhang等2013)。
但最近的研究证实, 在雌二醇诱导的tor突变体中,
雷帕霉素与拟南芥中AtFKBP12互作后, 与AtTOR
的结合抑制AtTOR的激酶活性(Xiong和Sheen
2012)。在转有ScFKBP12的拟南芥转基因植株中,
雷帕霉素通过ScFKBP12与AtTOR结合抑制AtTOR
的活性, 用雷帕霉素处理转基因植株, 发现多聚核
糖体的含量降低(Sormani等2007; Zhang等2013)。
在乙醇诱导的tor-RNAi突变体中, 多聚核糖体的含
量也明显降低(Deprost等2007), 表明AtTOR参与蛋
白质的翻译过程。结合之前的研究结果, RAP-
TOR-1/RAPTOR-2、LST8-1/LST8-2与AtTOR组成
AtTORC (AtTOR complex) (Anderson等2005;
Deprost等2005; Mahfouz等2006; Moreau等2012);
AtTOR可以磷酸化拟南芥中的S6K1和S6K2 (Turck
等2004; Xiong和Sheen 2012)。表明TOR途径在拟
南芥中也是保守的。
在植物中, 病毒侵染可以激活AtTOR促进病毒
35S mRNA的翻译再起始(Schepetilnikov等2011)。
Schepetilnikov等(2013)最近的一项研究证明AtTOR
直接和eIF3c (eIF3 complex)互作并磷酸化S6K1, 参
与蛋白翻译的再起始。免疫共沉淀结果显示 ,
eIF3c可以分别与AtTOR和S6K1结合, 用TOR的抑
制剂Torin-1处理后, eIF3c只与S6K1结合; 当加入
生长素类似物萘乙酸(1-naphthylacetic acid, NAA)
诱导AtTOR激活时, AtTOR磷酸化S6K1, eIF3c只与
AtTOR结合(Schepetilnikov等2013), 暗示植物中
AtTOR-S6K1参与蛋白翻译的作用机制可能和哺
乳动物中一样, 活化的AtTOR与eIF3c结合后磷酸
化S6K1, 使S6K1与eIF3c解离。
在拟南芥中没有发现4E-BP的同源蛋白, 但是
图2 TOR信号途径
Fig.2 TOR signaling pathways
4E-BP1和S6K1是mTORC1的2种直接底物,
可以被mTORC1磷酸化。翻译起始时, 4E-BP1与
eIF4E结合, 抑制eIF4F复合体(包括eIF4A、eIF4E
和eIF4G)的组成 , 翻译起始受阻 (Ma和Blenis
2009)。在正常情况下, 活化的mTORC1与eIF3结
合, 使S6K1磷酸化与eIF3解离; 进而mTORC1磷酸
化4E-BP1使其与eIF4E解离, 解除对翻译起始的抑
制(Holz等2005)。活化的S6K1磷酸化PDCD4 (pro-
grammed cell death 4), 解除PDCD4对eIF4A (有
mRNA解旋酶的作用 )的抑制作用 (Dorrel lo等
2006); 同时, 磷酸化eIF4B增强eIF4A的解旋酶活性
(Raught等2004), 促进mRNA的翻译(图2)。
与酵母和哺乳动物中不同的是, 植物对雷帕
霉素不敏感, 雷帕霉素不能像抑制酵母和哺乳动
物细胞一样抑制植物的生长(Menand等2002)。由
李厚华等: 植物蛋白质翻译水平的调控 163
酵母中蛋白磷酸酶2A (protein phosphatase 2A, PP2A)
的蛋白亚基Tap42在TOR信号途径的下游, 影响蛋
白翻译(Duvel和Broach 2004)。拟南芥中Tap42同
源蛋白Tap46与AtTOR互作, 体外磷酸化实验证实
AtTOR可磷酸化Tap46; 在TAP46沉默突变体中, 多
聚核糖体含量减少, 体内蛋白翻译水平降低(Ahn
等2011)。
3 TOR途径与GCN2-eIF2途径
TOR与eIF2并非是两条相互独立的控制蛋白
翻译的途径, 例如TOR和GCN2-eIF2途径都能响应
体内氨基酸水平的变化进而调控蛋白翻译(Don-
nelly等2013; Proud 2014)。然而TOR响应氨基酸缺
乏(图2) (Benjamin和Hall 2014; Demetriades等2014;
Deval等2009; Gallinetti等2013)与GCN2的作用机
制不同。mTORC1通过Rag蛋白的异二聚复合体
(RagA/B-RagC/D)感应体内氨基酸水平(图2) (San-
cak等2008); GCN2则是通过与空载tRNA结合感知
体内氨基酸水平的变化。目前在植物中尚未见到
TOR响应氨基酸缺乏的相关报道。
在酵母细胞中, TOR可调控GCN2的激活, 雷
帕霉素通过TOR-TAP42途径去除GCN2在S577的
磷酸化, 激活GCN2, 影响体内蛋白翻译水平(Cher-
kasova和Hinnebusch 2003) (图2); GCN2缺失的突
变体增强细胞对雷帕霉素的抗性(Narasimhan等
2004); TORC2-YPK1信号途径抑制钙调磷酸酶的
活性, 间接提高GCN2的磷酸化水平(Vlahakis等
2014)。在植物中, 有实验表明在AtTOR超表达及
沉默植株中, eIF2磷酸化水平不受影响(Lageix等
2008)。但植物中TOR与GCN2-eIF2途径之间是否
通过其他机制存在联系, 还有待进一步的研究。
4 展望
GCN2-eIF2与TOR途径在植物中是保守的, 二
者共同调控体内蛋白质的合成水平。已有的研究
发现植物中eIF2激酶只有GCN2, 而在哺乳动物中
有4种, 植物中是否还有其他eIF2α激酶存在, 尚有
待进一步探明。相对于哺乳动物而言 , 植物中
TOR参与蛋白翻译的研究较为滞后, 目前只发现
tor突变体中蛋白翻译整体水平降低, AtTOR-S6K1
途径参与蛋白翻译的再起始, 但系统的作用机制
还不清楚。另外, 植物中是否存在TOR/4E-BP1途
径参与蛋白翻译, TOR途径参与植物蛋白翻译的具
体作用机制等, 都有待进一步的研究。
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