Endoplasmic Reticulum Stress and Mammalian Male Reproduction

ISSN 1007-7626 CN 11-3870 / Q http / /cjbmb. bjmu. edu. cn Chinese Journal of Biochemistry and Molecular Biology 2016 8 32 8 879 ~ 885 DOI 10. 13865 /j. cnki. cjbmb. 2016. 08. 05 * * 712100 endoplasmic reticulum stress ERS ERS ERS ERS ERS ERS ERS ERS Q71 Endoplasmic Reticulum Stress and Mammalian Male Reproduction CUI Yan-Hua HUA Jin-Lian * PENG Sha * Shaanxi Centre of Stem Cells Engineering & Technology College of Veterinary Medicine Northwest A&F University Yangling 712100 Shaanxi China Abstract Endoplasmic reticulum stress ERS activates unfolded protein response in order to maintain homeostasis in mammalian cells however excessive or persistent ERS results in cellular apoptosis. According to the latest progress ERS plays an important role in regulating testicular structure and spermatogenesis of the male reproduction system in mammals. ERS is a novel pathway involved in regulating the survival and apoptosis of germ cells. Excessive ERS has been reported to contribute to male infertility. Here we briefly summarize recent studies in the roles of ERS in inflammation apoptosis and infertility of the male reproductive system which may offer insights towards potential modulation of ERS to treat male reproductive diseases. Key words endoplasmic reticulum stress ERS male reproduction mammal endoplasmic reticulum ER ERS 1 2 2016-01-30 2016-03-09 2016-03-23 No. 31272518 No. 31572799 863 No. SS2014AA021605 3 endoplasmic reticulum * Tel 029-87080068 E-mail jinlianhua@ nwsuaf. edu. cn stress ERS unfolded protein response UPR 4 UPR UPR 5 6 pengshacxh@ 163. com Received January 30 2016 Revised March 9 2016 Accepted March 23 2016 Supported by National Natural Science Foundation of China No. 31272518 No. 31572799 and National High Technology Research and Development Program of China 863 Program No. SS2014AA021605 * Corresponding author Tel 029-87080068 E-mail jinlianhua@ nwsuaf. edu. cn pengshacxh@ 163. com

880 32 ERS 8 ERS Ca 2 + 1 ERS B 7 ERS 10 11 ERS 9 ERS Fig. 1 Endoplasmic reticulum stress signaling The figure represents three branches of ERS. The ERS response is mediated by three sensors located at the ER membrane PERK IRE1α and ATF6. Accumulation of unfolded protein recruits GRP78 BiP to the ER lumen and its dissociation from IRE1α ATF6 and PERK leads to their activation Fig. 2 Spermatogenesis in mammals Spermatogenesis originates from spermatogonia which resides on the basement membrane of the seminiferous tubules. Spermatogonia mitotically divides into spermatocyte and this stage is followed by meiosis and the formation of mature spermatozoa ER ER ER UPR 12 UPR Fig. 1 UPR 3 PKR PKR-like ER kinase PERK 6 activating transcription factor 6 ATF6-1 inositol-requiring enzyme 1 IRE-1 PERK ATF6 IRE-1 N BiP C 1. 1 ERS 13 14 3 78 GRP78 /BiP ERS

8 881 BiP UPR UPR 2 ERS 13 UPR UPR ER Fig. 2 1 ER ERS UPR 2 2 4 ERS 15 1. 2 ERS ERS ERS 3 26 UPR PERK ERS ERS 2a eukaryotic translation initiation factor 2a eif-2a PERK ER ERS 16 27 ATF4 ATF4 C /EBP ER C /EBP-homologous protein CHOP GADD34 eif-2a ATF4 ERS GADD34 CHOP 17 CHOP 18 IRE1 IRE-1 X 1 X box protein 1 XBP1 mrna 19 XBP1s Table 1 ER 2. 1 ERS 20 IRE1 IRE-1 2 TNF-receptorassociated factor 2 TRAF2 TRAF2-IRE1 29 κb apoptosis signal regulated kinase ASK1 21 nuclear factor-κb NF-κB C-Jun N- c-jun NH2-terminal kinases JNK Bcl-2 19 tumor necrosis factor-α TNF-α JNK BAX BIM 1β interleukin-1β IL-1β UPR ERS inducible nitric oxide synthase inos UPR 2 cyclooxygenase-2 COX-2 31 PERK IRE-1 22 23 ERS ATF6 33 ATF6 BiP GRP94 XBP1 24 3 25 ERS

882 32 36 Table 1 Recent studies in the roles of ERS in male reproductive system Author Pathologies Major progress Method Reference Kim et al. Testicular heat stress Heat induced ER-stress significantly influences steroidogenic enzyme expression and testosterone production in the Leydig cells 28 Li et al Germ cell apoptosis Endoplasmic reticulum stress attributed to the apoptosis of testicular germ cells in hyperlipidemic rats TUNEL staining Immunohistochemistry RT-PC 29 Chow et al Male infertility Excessive ERS in the accessory gland would perturb normal secretory function and result in a large decrease in SFP production and male infertility 30 Rashid et al Testicular damage Curcumin ameliorates testicular damage in diabetic rats by suppressing cellular endoplasmic reticulum stress Western blot 31 Ji et al Germ cell apoptosis Phenylbutyric acid PBA an ER chemical chaperone attenuated Cdinduced ER stress and protected against germ cell apoptosis in testes TUNEL staining Western blot Immunohistochemistry 32 Skibba et al. Germ cell death Non-mitogenic acidic FGF-1 may alleviate diabetes-induced germ cell death by decreasing the BAX /Bcl-2 ratio and endoplasmic reticulum stress Zhang et al. Germ cell loss ER stress and inflammation would be significant mechanisms responsible for fluoride-induced disturbance of spermatogenesis and germ cell loss 33 34 Liu et al. Male hypogonadism Male hypogonadism induced by high fat diet and low dose streptozotocin is mediated by activated endoplasmic reticulum stress RT-PCR Western blot 35 TUNEL mrna TNF-α IL-1β NF-κB 37 ERS NF-κB ERS ERS 38 Zhang 34 ERS GRP78 IRE1 CHOP 2. 2 ERS HE

8 883 2. 3 ERS 39 40 ERS caspase- ERS ERS 12 caspase-4 caspase-7 41 ERS 3 ERS C AG c-abl ERS ERS Xbp1 Xbp1 C protein kinase C PKC 42 Ca 2 + splicing Xbp1s ERS Xbp1 mrna Bax Bak IRE1 Xbp1s UPR Ca 2 + Bax Ca 2 + 19 Xbp1s UPR 47 C 43 ERS Xbp1s seminal fluid proteins SFPs 30 ERS ERS GRP78 ATF6 ERS PERK eif2α Leydig CHOP bim bax ERS GRP78 /BIP CHOP bad ERS 3β-HSD PBA Western p-eif-2α ERS CHOP p-jnk PBA TUDCA GRP78 CHOP 3β-HSD ERS 32 ERS AIF Leydig poly ADP-ribose polymerase-1 PARP-1 46 AG UPR BiP 28 Leydig 44 PARP-1 ERS UPR PARP-1 DNA Leydig PARP-1 AIF PARP-1 ER 45 Ca 2 + ERS ER UPR Ca 2 + ERS ERS-responsive PLC /PKC PI3K MAPK PLC /IP3 genes ERSRG Ca 2 + Ca 2 + 48 ERS

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