摘要内质网(ER)细胞内的Ca2+储存场所是细胞内最大的膜性细胞器,控制着细胞内大量蛋白的加工、修饰及合成。其上有很多的分子伴侣蛋白(如凝集素,折叠酶等)来帮助分泌蛋白、膜蛋白形成二硫键和糖基化修饰,维持蛋白的正确折叠和转位。当具备氧化特性和高钙离子浓度特性的内质网内环境遭到破坏既导致不能正确折叠的蛋白质在内质网中聚集从而导致严重的内质网应激(ERS)压力。位于内质网膜的跨膜受体分子通过感知内质网应激压力信号而起始非正确折叠蛋白应答(UPR)以修复内质网的功能。近年来,随着对 ERS 研究的深入,有研究发现ERS可能参与生殖生理及病理疾病中某些环节的调控,并与生殖系统疾病的发生,发展等关系密切。本文主要介绍内质网应激在生殖疾病中的研究进展,为进一步研究其生殖调控的机制提供新的思路。
1 Wang X,Eno CO,Altman BJ,et al.ER stress modulates cellular metabolism.Biochem J,2011,435:285-296. 2 Hasnain SZ,Lourie R,Das I,et al.The interplay between endoplasmic reticulum stress and inflammation.Immunol Cell Biol,2012,90:260-270 . 3 Glembotski CC.Endoplasmic reticulm stress in the heart.Circ Res,2007,101:975-984. 4 Meeker JD,Rossano MG,Protas B,et al.Cadmium,lead,and other metals in relation to semen quality:human evidence for molybdenum as a male reproductive toxicant.Environ Health Perspect,2008,116:1473-1479. 5 Jheng JR,Ho JY,Horng JT.ER stress,autophagy,and RNA viruses.Front Microbiol,2014,5:388. 6 Luo D,He Y,Zhang H,et al.AIP1 1 is critical in transducing IRE1-mediated endoplasmic reticulum stress response.J Biol Chem,2011,283:11905-11912. 7 Fung TS,Liu DX.Coronavirus infection,ER stress,apoptosis andinnate immunity.Front Microbiol,2014,5:296. 8 Yoshida H,Matsui T,Yaraaraoto A,et al.XBPl mRNA is induced by ATF6 and splicedby IREl in response to ER stress to produce a highly active transcription factor.Cell,2001,107:881-891. 9 Lee AH,Iwakoshi NN,Glimcher LH.XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response.MolCell Biol,2003,23:7448-7459. 10 Sheveleva EV,Landowski TH,Samulitis BK,et al.Imexon induces an oxidative endoplasmic reticulum stress response in pancreatic cancer cells.Mol Cancer Res,2012,210:392-400. 11 Tobiume K,Saitoh M,Ichijo H.Activation of apoptosis signal-regulating kinase 1 by the stress-induced activating phosphorylation of pre-formed oligomer.J Cell Physiol,2002,191:95-104. 12 Matsuzawa A,Ichijo H.Redox control of cell fate by MAP kinase:physiological roles of ASK1-MAP kinase pathway in stress signaling.Biochim Biophys Acta,2008,1780:1325-1336. 13 Gu JJ,Wang Z,Reeves R,et al.PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis.Oncogene,2009,28:4261-4271. 14 Marciniak SJ,Garcia-Bonilla L,Hu J,et al.Activation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK.J Cell Biol,2006 172:201-209. 15 Shi Y,Vattem KM,Sood R,et al.Identification and characterization of pancreatic eukaryotic initiation factor 2 α-subunit kinase,PEK,involved in translational control.Mol Cell Biol,1998,18:7499-7509. 16 Harding HP,Novoa I,Zhang Y,et al.Regulated translation initiation controlsstress-induced gene expression in mammalian cells.Mol Cell,2000,6:1099-1108. 17 Szegezdi E,Logue SE,Gorman AM,et al.Mediators of endoplasmic reticulum stress-induced apoptosis .EMBO Rep,2006,7:880-885. 18 Marciniak SJ,Ron D.Endoplasmic reticulum stress signaling in disease.Physiol Rev,2006,86:1133-1149. 19 Novoa I,Zeng H,Harding HP,et al.Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha.J Cell Biol,2001,153:1011-1022. 20 Marciniak SJ,Yun CY,Oyadomari S,et al.CHOP induces death by promoting proteinsynthesis and oxidation in the stressed endoplasmic reticulum.Genes Dev,2004,18:3066-3077. 21 Ghosh AP,Klocke BJ,Ballestas ME,et al.CHOP potentially co-operates with FOXO3a in neuronal cells to regulate PUMA and BIM expression in response to ER stress.PLoS One,2012,7:e39586. 22 Kiviluoto S,Vervliet T,Ivanova H,et al.Regulation of inositol 1,4,5-trisphosphate receptors during endoplasmic reticulum stress.Biochim Biophys Acta,2013,1833:1612-1624. 23 Chen YH,Wu XD,Yao ST,et al.Calcineurin is involved in car-dioprotection induced by ischemic postconditioning through attenu-atingendoplasmic reticulum stress.Chin Med J (Engl),2011,124:3334-3340. 24 Kim EM,Shin EJ,Choi JH,et al.Matrix metalloproteinase-3 is increased and participates in neuronal apoptotic signalingdownstream of caspase-12 during endoplasmic reticulum stress.J Biol Chem,2010,285:16444-16452. 25 Liu D,Zhang M,Yin H.Signaling path ways involved in endoplasmic reticulum stress induced neuronal apoptosis.Int J Neurosci,2013,123:155-162. 26 Rao RV,Peel A,Logvinova A,et al.Coupling endoplasmic reticulum stress to the cell death program:roleof the ER chaperone GRP78.FEBS Lett,2002,5:122-128. 27 Bian ZM,Elner SG,Elner VM.Dual involvement of caspase-4 in inflammatory andER stress-induced apoptotic responses in human retinal pigment epithelial cells.Invest Ophthalmol Vis Sci,2009,50:6006-6014. 28 Yamamuro A,Kishino T,Ohshima Y,et al.Caspase-4 directly activates caspase-9in endoplasmic reticulum stress-induced apoptosis in SH-SY5Y cells.JPharmacol Sci,2011,115:239-243. 29 Reddy RK,Mao C,Baumeister P,et al.Endoplasmic reticulum chaperone proteinGRP78 protects cells from apoptosis induced by topoisomerase inhibitors:roleof ATP binding site in suppression of caspase-7 activation.J Biol Chem,2003,278:20915-20924. 30 Li C,Wei J,Li Y,et al.TMEM214 mediates ER stress-induced caspse-4 activation and apoptosis.J Biol.Chem,2013,14:17908-17917. 31 Luo S,Mao C,Lee B,et al.GRP78/BiP is required for cell proliferation and protecting the inner cell mass from apoptosis during early mouse embryonic development.Mol Cell Biol,2006,26:5688-5697. 32 Kawakami T,Yoshimi M,Kadota Y,et al.Prolonged endoplasmic reticulumstress alters placentalmorphology and causes low birth weight.Toxicol Appl Pharmacol,2014,275:134-144. 33 Lian IA,Lset M,Mundal SB,et al.Increased endoplasmic reticulum stress in decidual tissue from pregnancies complicated by fetal growth restriction with and without preeclampsia.Placenta,2011,32:823-829. 34 Iwawaki T,Akai R,Yamanaka S,et al.Function of IRE 1 alpha in the placenta is essential for placental development and embryonic viability.Proceedings of the National Academy of Sciences,2009,106:16657-16658. 35 Abraham T,Pin CL,Watson AJ.Embryo collection induces transient activation of XBP1 arm of the ER stress response while embryo vitrification does not .Molecular human reproduction,2012,18:229-242. 36 Wang Z,Wang H,Xu ZM.Cadmium-induced teratogenicity:association with ROS-mediated endoplasmic reticulum stress in placenta.Toxicol Appl Pharmacol,2012,259:236-247. 37 李政达.牛磺熊脱氧胆酸对黄牛卵母细胞体外成熟及早期胚胎发育影响的研究.广西:广西大学,2014. 38 Lin P,Yang Y,Li X,et al.ERS involved in the granulosa cell apoptosis during follicle atresia.Melocular reproduction and development.Mol Reprod Dev,2012,79:423-432. 39 尹娇娇.EGF通过内质网应激通路调控山羊卵泡颗粒细胞凋亡的作用研究.西安:西北农林科技大学,2014. 40 Xu X,Liu T,Zhang A.Reactive Oxygen Species-triggered trophoblast apoptosis is initiated by ER stress via activation of caspase12,CHOP and the JNK pathway in Toxoplasma gondii infection in mice.Infection and Immunity ,2012,80:2121-2132. 41 Burton GJ,Yung HW,Cindrova-Davies T,et al.Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia.Placenta,2009,30:43-48. 42 Lset M,Mundal SB,Johnson MP,et al.A transcriptional profile of the decidua in preeclampsia.Am J Obstet Gynecol,2011,204:1-27. 43 乌兰,石中华,王小青.胎盘内质网应激相关蛋白Calnexin与子痫前期发病的关系.江苏医药,2011,37:1895-1896. 44 欧阳煜宏,李晨阳,姚瑾,等.内质网应激介导的细胞凋亡在子宫内膜异位症发病中的作用研究.中国实用妇科与产科杂志,2012,28:218-221. 45 常玉华,李坤.子痫前期患者胎盘中miRNA-101和内质网蛋白ERp44的表达和意义.中国生化药物杂志,2014,34:38-43.
