The endoplasmic reticulum(ER)is the site of entry of all proteins that function in the secretory pathway including the extracellular environment.Because it controls the folding of newly synthesized secretory proteins,...The endoplasmic reticulum(ER)is the site of entry of all proteins that function in the secretory pathway including the extracellular environment.Because it controls the folding of newly synthesized secretory proteins,the ER is indispensable for the maintenance of proteostasis in the secretory pathway.Within the ER and,in part,in post-ER compartments,the quality control of protein folding is under the regulation of the unfolded protein response(UPR)pathways.The UPR strategy is to enhance protein folding,increase the ER degradation pathway of misfolded proteins,and allow the exit from the ER of only correctly folded proteins.The latter is controlled by the multimeric complex COPII,which also provides some of the components for ER-phagy the only route for the disposal of protein aggregates.In this overview,we wish to contribute to the introduction of new perspectives in the study of the mechanisms underlying the control of proteostasis within the secretory pathway.展开更多
Foods and animal feeds frequently become contaminated with the nephrotoxic ochratoxin A(OTA).Our prior research has indicated that ursolic acid(UA),which is widely present in fruits and medicinal plants,has the potent...Foods and animal feeds frequently become contaminated with the nephrotoxic ochratoxin A(OTA).Our prior research has indicated that ursolic acid(UA),which is widely present in fruits and medicinal plants,has the potential to alleviate nephrotoxicity triggered by OTA.Additionally,excessive induction of endoplasmic reticulum(ER)-phagy exacerbates OTA-induced apoptosis.Therefore,further investigation is essential to comprehend whether UA can mitigate OTA-induced apoptosis by influencing ER-phagy.This objective is accomplished through a series of experiments involving assessments of cell viability,apoptosis,fluorescence microscopy,and western blot analysis.The outcomes of these experiments reveal that pre-treatment with 4μmol/L UA for 2 h can markedly reverse the elevated apoptotic rate,the co-localization of ER and lysosomes,and the protein expressions of GRP78,p-eIF2α,Chop,Bax,and Bak,as well as the reduced cell viability and the protein expressions of Lonp1,Trap1,p62,Tex264,FAM134B,Bcl-2,and Bcl-xl,all caused by exposure to 1μmol/L OTA for 24 h in human proximal tubule epithelial-originated kidney-2(HK-2)cells(P<0.05).Interestingly,the increased expression of LC3B-II induced by OTA is further amplified by UA pre-treatment(P<0.05).In conclusion,OTA triggers a harmful feedback loop between ER stress(ERS)and excessive ER-phagy,thereby further promoting ERS-and mitochondrial-mediated apoptosis in vitro.However,this effect is significantly mitigated by UA through the inhibition of autophagosome-lysosome fusion,consequently blocking the excessive ER-phagic flux.展开更多
基金This work was supported by POR FERS Regione Campania 2014–2020 ASSE 1 O.S 1.2grant System Innovation for Cancer Early Diagnosis(SICED).
文摘The endoplasmic reticulum(ER)is the site of entry of all proteins that function in the secretory pathway including the extracellular environment.Because it controls the folding of newly synthesized secretory proteins,the ER is indispensable for the maintenance of proteostasis in the secretory pathway.Within the ER and,in part,in post-ER compartments,the quality control of protein folding is under the regulation of the unfolded protein response(UPR)pathways.The UPR strategy is to enhance protein folding,increase the ER degradation pathway of misfolded proteins,and allow the exit from the ER of only correctly folded proteins.The latter is controlled by the multimeric complex COPII,which also provides some of the components for ER-phagy the only route for the disposal of protein aggregates.In this overview,we wish to contribute to the introduction of new perspectives in the study of the mechanisms underlying the control of proteostasis within the secretory pathway.
基金financially supported by the National Natural Science Foundation of China(82060598,32260587)the Natural Science Foundation of Guizhou Province(QKH-J-ZK[2021]181)+4 种基金the Scientific Research Program of Guizhou Provincial Department of Education(QJJ[2023]019)the Science&Technology Program of Guizhou Province(QKHPTRC-CXTD[2022]014)the Excellent Youth Talents of Zunyi Medical University(17zy-006)the Innovation and Entrepreneurship Training Program for College Students of Guizhou Province(S202210661138)the Innovation and Entrepreneurship Training Program for College Students of Zunyi Medical University(ZYDC2021108)。
文摘Foods and animal feeds frequently become contaminated with the nephrotoxic ochratoxin A(OTA).Our prior research has indicated that ursolic acid(UA),which is widely present in fruits and medicinal plants,has the potential to alleviate nephrotoxicity triggered by OTA.Additionally,excessive induction of endoplasmic reticulum(ER)-phagy exacerbates OTA-induced apoptosis.Therefore,further investigation is essential to comprehend whether UA can mitigate OTA-induced apoptosis by influencing ER-phagy.This objective is accomplished through a series of experiments involving assessments of cell viability,apoptosis,fluorescence microscopy,and western blot analysis.The outcomes of these experiments reveal that pre-treatment with 4μmol/L UA for 2 h can markedly reverse the elevated apoptotic rate,the co-localization of ER and lysosomes,and the protein expressions of GRP78,p-eIF2α,Chop,Bax,and Bak,as well as the reduced cell viability and the protein expressions of Lonp1,Trap1,p62,Tex264,FAM134B,Bcl-2,and Bcl-xl,all caused by exposure to 1μmol/L OTA for 24 h in human proximal tubule epithelial-originated kidney-2(HK-2)cells(P<0.05).Interestingly,the increased expression of LC3B-II induced by OTA is further amplified by UA pre-treatment(P<0.05).In conclusion,OTA triggers a harmful feedback loop between ER stress(ERS)and excessive ER-phagy,thereby further promoting ERS-and mitochondrial-mediated apoptosis in vitro.However,this effect is significantly mitigated by UA through the inhibition of autophagosome-lysosome fusion,consequently blocking the excessive ER-phagic flux.
