内质网应激的信号通路及其与细胞凋亡相关疾病关系的研究进展
摘要
细胞凋亡是指生理性或者病理性因素触发细胞内预存的死亡程序,内质网应激(ERS)在细胞凋亡过程中发挥着重要作用。氧化应激、Ca2+稳态失衡及缺氧等可引起蛋白质在内质网内的折叠受到抑制,促使未折叠蛋白聚集,引起ERS,激活未折叠蛋白反应,若此反应持续存在,则可诱发细胞凋亡。ERS包括PERK、IRE1、ATF6三条经典的信号通路,由PERK介导的信号通路能快速减少蛋白质的合成,减轻内质网的负荷; IRE1和ATF6介导的信号通路能增加内质网分子伴侣蛋白的合成,增加内质网蛋白的折叠、转运和降解的能力,减轻内质网的负荷。ERS参与了心肌缺血再灌注损伤、衰老、骨质疏松、肝硬化、肿瘤等疾病的发生发展,针对ERS进行干预有望成为治疗凋亡相关疾病的重要靶点。
引文
[1] Wang K. Molecular mechanisms of hepatic apoptosis[J]. Cell Death Dis,2014,5(1):e996.
[2]Almanza A,Carlesso A,Chintha C,et al. Endoplasmic reticulum stress signaling-from basic mechanisms to clinical applications[J].FEBS J,2018,19(12):3905.
[3]陈娜子,姜潮,李校堃.内质网应激与疾病[J].中国生物工程杂志,2016,36(1):76-85.
[4]Mennerich D,Kellokumpu S,Kietzmann T. Hypoxia and reactive oxygen species as modulators of endoplasmic reticulum and Golgi homeostasis[J]. Antioxid Redox Signal,2019,30(1):113-137.
[5]李欲轲,熊孟连,徐僡,等.内质网应激与凋亡研究进展[J].分子植物育种,2018,9(1):1-8.
[6]宋小燕,赵永波.未折叠蛋白反应与细胞转归[J].神经疾病与精神卫生,2010,10(4):99-102.
[7]Hetz C,Chevet E,Harding HP. Targeting the unfolded protein response in disease[J]. Nat Rev Drug Discov,2013,12(9):703-719.
[8]Bertolotti A,Zhang Y,Hendershot LM,et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response[J]. Nat Cell Bioly,2000,2(6):326-332.
[9]李明,丁健,缪泽鸿.未折叠蛋白反应的信号转导[J].生命科学,2008,20(2):246-252.
[10]Smith M,Wilkinson S. ER homeostasis and autophagy[J]. Essays Biochem,2017,61(6):625-635.
[11]Mennerich D,Kellokumpu S,Kietzmann T. Hypoxia and reactive oxygen species as modulators of endoplasmic reticulum and Golgi homeostasis[J]. Antioxid Redox Signal,2019,30(1):113-137.
[12]Almanza A,Carlesso A,Chintha C,et al. Endoplasmic reticulum stress signalling-from basic mechanisms to clinical applications[J]. FEBS J,2019,286:241-278.
[13]Huang Q,Lan T,Lu J,et al. Di Dang tang inhibits endoplasmic reticulum stress-mediated apoptosis induced by oxygen glucose deprivation and intracerebral hemorrhage through blockade of the GRP78-IRE1/PERK pathways[J]. Front Pharmacol,2018,9:1423.
[14]Carew NT,Nelson AM,Liang Z,et al. Linking endoplasmic reticular stress and alternative splicing[J]. Int J Mol Sci,2018,19(12):1-13.
[15]Rashid HO,Kim HK,Junjappa R,et al. Endoplasmic reticulum stress in the regulation of liver diseases:involvement of regulated IRE1αandβ-dependent decay and miRNA[J]. J Gastroenterol Hepatol,2017,32:981-991.
[16]张毓,孟凤琴,张蔷,等.内质网应激因子ATF6在hSOD1G93A转基因小鼠脊髓中的表达[J].脑与神经疾病杂志,2016,24(3):160-165.
[17]Chiang WC,Chan P,Wissinger B,et al. Achromatopsia mutations target sequential steps of ATF6 activation[J]. Proc Natl Acad Sci U S A,2017,114:400-405.
[18] Chan P,Stolz J,Kohl S,et al. Endoplasmic reticulum stress in human photoreceptor diseases[J]. Brain Res,2016,1648:538-541.
[19] Papaioannou A,Higa A,Jégou G,et al. Alterations of EDEM1functions enhance ATF6 pro-survival signaling[J]. FEBS J,2018,285:4146-4164.
[20]Zhang C,Tang Y,Li Y,et al. Unfolded protein response plays a critical role in heart damage after myocardial ischemia/reperfusion in rats[J]. PLo S One,2017,12(6):e0179042.
[21]Martindale JJ,Fernandez R,Thuerauf D,et al. Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6[J]. Circ Res,2006,98:1186-1193.
[22]Jin JK,Blackwood EA,Azizi K,et al. ATF6 decreases myocardial ischemia/reperfusion damage and links ER stress and oxidative stress signaling pathways in the heart[J]. Circ Res,2017,120:862-875.
[23]Zhao D,Feng P,Sun Y,et al. Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis[J]. Cell Death Dis,2018,9:723.
[24]马娜,张长城,陈茜,等.基于内质网应激研究五子衍宗方对自然衰老大鼠睾丸生殖细胞凋亡的保护作用[J].中国中药杂志,2018,43(19):3899-3904.
[25]阮波,王东帆,张长城,等.从内质网应激途径探讨竹节参总皂苷对自然衰老大鼠脑组织的保护作用[J].中药材,2017,40(8):1930-1934.
[26]王佼,袁丁,宋亚男,等.从内质网应激途径探讨淫羊藿总黄酮对衰老大鼠心肌细胞的保护作用[J].中药新药与临床药理,2016,27(6):745-750.
[27]刘敏,顿耀艳,彭丹丽,等.从内质网应激角度研究竹节参总皂苷对自然衰老大鼠结肠炎症反应的调节作用[J].中药材,2017,40(2):425-429.
[28]Mc Laughlin T,Falkowski M,Park JW,et al. Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration[J]. Mol Neurodegener,2018,13:16.
[29]Wang W,Sun Y,Chen S,et al. Impaired unfolded protein response in the degeneration of cochlea cells in a mouse model of age-related hearing loss[J]. Exp Gerontol,2015,70:61-70.
[30]芮敏劼,郑苏阳,郭杨,等.内质网应激通路与骨质疏松相关性的研究进展[J].医学研究生学报,2016,29(8):877-882.
[31]Kim JH,Kim K,Kim I,et al. Endoplasmic reticulum-bound transcription factor CREBH stimulates RANKL-induced osteoclastogenesis[J]. J Immunol,2018,200:1661-1670.
[32]Zhang K,Wang M,Li Y,et al. The PERK-EIF2α-ATF4 signaling branch regulates osteoblast differentiation and proliferation by PTH[J]. Am J Physiol Endocrinol Metab,2019,316(4):E590-604.
[33]潘高峰,傅茂英,郜玉峰.内质网应激与肝纤维化关系研究进展[J].实用肝脏病杂志,2018,21(6):987-990.
[34] Zuo L,Zhu Y,Hu L,et al. PI3-kinase/Akt pathway-regulated membrane transportation of acid-sensing ion channel 1a/Calcium ion influx/endoplasmic reticulum stress activation on PDGF-induced HSC activation[J]. J Cell Mol Med,2019.[Epub ahead of print]
[35]Li Y,Yan Y,Liu F,et al. Effects of calpain inhibitor on the apoptosis of hepatic stellate cells induced by calcium ionophore A23187[J]. J Cell Biochem,2018.[Epub ahead of print]
[36]Feldman DE. The unfolded protein response:a novel component of the hypoxic stress response in tumors[J]. Mol Cancer Res,2005,3(11):597-605.
[37]Song M,Sandoval TA,Chae CS,et al. IRE1α-XBP1 controls T cell function in ovariancancer by regulating mitochondrial activity[J]. Nature,2018,562:423-428.
[38]Xu D,Liang SQ,Yang H,et al. Increased sensitivity to apoptosis upon endoplasmic reticulum stress-induced activation of the unfolded protein response in chemotherapy-resistant malignant pleural mesothelioma[J]. Br J Cancer,2018,119:65-75.
[2]Almanza A,Carlesso A,Chintha C,et al. Endoplasmic reticulum stress signaling-from basic mechanisms to clinical applications[J].FEBS J,2018,19(12):3905.
[3]陈娜子,姜潮,李校堃.内质网应激与疾病[J].中国生物工程杂志,2016,36(1):76-85.
[4]Mennerich D,Kellokumpu S,Kietzmann T. Hypoxia and reactive oxygen species as modulators of endoplasmic reticulum and Golgi homeostasis[J]. Antioxid Redox Signal,2019,30(1):113-137.
[5]李欲轲,熊孟连,徐僡,等.内质网应激与凋亡研究进展[J].分子植物育种,2018,9(1):1-8.
[6]宋小燕,赵永波.未折叠蛋白反应与细胞转归[J].神经疾病与精神卫生,2010,10(4):99-102.
[7]Hetz C,Chevet E,Harding HP. Targeting the unfolded protein response in disease[J]. Nat Rev Drug Discov,2013,12(9):703-719.
[8]Bertolotti A,Zhang Y,Hendershot LM,et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response[J]. Nat Cell Bioly,2000,2(6):326-332.
[9]李明,丁健,缪泽鸿.未折叠蛋白反应的信号转导[J].生命科学,2008,20(2):246-252.
[10]Smith M,Wilkinson S. ER homeostasis and autophagy[J]. Essays Biochem,2017,61(6):625-635.
[11]Mennerich D,Kellokumpu S,Kietzmann T. Hypoxia and reactive oxygen species as modulators of endoplasmic reticulum and Golgi homeostasis[J]. Antioxid Redox Signal,2019,30(1):113-137.
[12]Almanza A,Carlesso A,Chintha C,et al. Endoplasmic reticulum stress signalling-from basic mechanisms to clinical applications[J]. FEBS J,2019,286:241-278.
[13]Huang Q,Lan T,Lu J,et al. Di Dang tang inhibits endoplasmic reticulum stress-mediated apoptosis induced by oxygen glucose deprivation and intracerebral hemorrhage through blockade of the GRP78-IRE1/PERK pathways[J]. Front Pharmacol,2018,9:1423.
[14]Carew NT,Nelson AM,Liang Z,et al. Linking endoplasmic reticular stress and alternative splicing[J]. Int J Mol Sci,2018,19(12):1-13.
[15]Rashid HO,Kim HK,Junjappa R,et al. Endoplasmic reticulum stress in the regulation of liver diseases:involvement of regulated IRE1αandβ-dependent decay and miRNA[J]. J Gastroenterol Hepatol,2017,32:981-991.
[16]张毓,孟凤琴,张蔷,等.内质网应激因子ATF6在hSOD1G93A转基因小鼠脊髓中的表达[J].脑与神经疾病杂志,2016,24(3):160-165.
[17]Chiang WC,Chan P,Wissinger B,et al. Achromatopsia mutations target sequential steps of ATF6 activation[J]. Proc Natl Acad Sci U S A,2017,114:400-405.
[18] Chan P,Stolz J,Kohl S,et al. Endoplasmic reticulum stress in human photoreceptor diseases[J]. Brain Res,2016,1648:538-541.
[19] Papaioannou A,Higa A,Jégou G,et al. Alterations of EDEM1functions enhance ATF6 pro-survival signaling[J]. FEBS J,2018,285:4146-4164.
[20]Zhang C,Tang Y,Li Y,et al. Unfolded protein response plays a critical role in heart damage after myocardial ischemia/reperfusion in rats[J]. PLo S One,2017,12(6):e0179042.
[21]Martindale JJ,Fernandez R,Thuerauf D,et al. Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6[J]. Circ Res,2006,98:1186-1193.
[22]Jin JK,Blackwood EA,Azizi K,et al. ATF6 decreases myocardial ischemia/reperfusion damage and links ER stress and oxidative stress signaling pathways in the heart[J]. Circ Res,2017,120:862-875.
[23]Zhao D,Feng P,Sun Y,et al. Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis[J]. Cell Death Dis,2018,9:723.
[24]马娜,张长城,陈茜,等.基于内质网应激研究五子衍宗方对自然衰老大鼠睾丸生殖细胞凋亡的保护作用[J].中国中药杂志,2018,43(19):3899-3904.
[25]阮波,王东帆,张长城,等.从内质网应激途径探讨竹节参总皂苷对自然衰老大鼠脑组织的保护作用[J].中药材,2017,40(8):1930-1934.
[26]王佼,袁丁,宋亚男,等.从内质网应激途径探讨淫羊藿总黄酮对衰老大鼠心肌细胞的保护作用[J].中药新药与临床药理,2016,27(6):745-750.
[27]刘敏,顿耀艳,彭丹丽,等.从内质网应激角度研究竹节参总皂苷对自然衰老大鼠结肠炎症反应的调节作用[J].中药材,2017,40(2):425-429.
[28]Mc Laughlin T,Falkowski M,Park JW,et al. Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration[J]. Mol Neurodegener,2018,13:16.
[29]Wang W,Sun Y,Chen S,et al. Impaired unfolded protein response in the degeneration of cochlea cells in a mouse model of age-related hearing loss[J]. Exp Gerontol,2015,70:61-70.
[30]芮敏劼,郑苏阳,郭杨,等.内质网应激通路与骨质疏松相关性的研究进展[J].医学研究生学报,2016,29(8):877-882.
[31]Kim JH,Kim K,Kim I,et al. Endoplasmic reticulum-bound transcription factor CREBH stimulates RANKL-induced osteoclastogenesis[J]. J Immunol,2018,200:1661-1670.
[32]Zhang K,Wang M,Li Y,et al. The PERK-EIF2α-ATF4 signaling branch regulates osteoblast differentiation and proliferation by PTH[J]. Am J Physiol Endocrinol Metab,2019,316(4):E590-604.
[33]潘高峰,傅茂英,郜玉峰.内质网应激与肝纤维化关系研究进展[J].实用肝脏病杂志,2018,21(6):987-990.
[34] Zuo L,Zhu Y,Hu L,et al. PI3-kinase/Akt pathway-regulated membrane transportation of acid-sensing ion channel 1a/Calcium ion influx/endoplasmic reticulum stress activation on PDGF-induced HSC activation[J]. J Cell Mol Med,2019.[Epub ahead of print]
[35]Li Y,Yan Y,Liu F,et al. Effects of calpain inhibitor on the apoptosis of hepatic stellate cells induced by calcium ionophore A23187[J]. J Cell Biochem,2018.[Epub ahead of print]
[36]Feldman DE. The unfolded protein response:a novel component of the hypoxic stress response in tumors[J]. Mol Cancer Res,2005,3(11):597-605.
[37]Song M,Sandoval TA,Chae CS,et al. IRE1α-XBP1 controls T cell function in ovariancancer by regulating mitochondrial activity[J]. Nature,2018,562:423-428.
[38]Xu D,Liang SQ,Yang H,et al. Increased sensitivity to apoptosis upon endoplasmic reticulum stress-induced activation of the unfolded protein response in chemotherapy-resistant malignant pleural mesothelioma[J]. Br J Cancer,2018,119:65-75.