Brassinosteroids(BRs)are essential phytohormones that broadly regulate plant growth,development,and adaptation to biotic and abiotic stresses.In Arabidopsis,apoplastic BR molecules are perceived by a plasma membrane-l...Brassinosteroids(BRs)are essential phytohormones that broadly regulate plant growth,development,and adaptation to biotic and abiotic stresses.In Arabidopsis,apoplastic BR molecules are perceived by a plasma membrane-localized receptor complex comprising the ligand-binding receptor BRI1 and the co-receptor BAK1.While negative regulators of the BR receptor complex,such as BKI1,BIR3,and PUB12/13,have been well characterized,how BRI1 and BAK1 are positively modulated in the BR pathway remains largely unknown.In this study,a genetic screen involving overexpression of RLP genes in the bak1-3 bkk1-1 double mutant reveals that enhanced RLP51 expression partially suppresses the BR-deficient phenotypes of bak1-3 bkk1-1.RLP51 overexpression also partially rescues the weak bri1 mutant allele,bri1-301.Although the rlp51 single mutant exhibits wild-type-like phenotypes,it enhances BR-defective phenotypes in bri1-301 and bak1 serk1 mutants.RLP51 is next found to interact with both BRI1 and BAK1 without affecting BRI1–BAK1 interaction.Critically,co-expression of RLP51 with BRI1 or BAK1 significantly increases BRI1 and BAK1 protein abundances.RLP51 appears to promote protein synthesis rather than stabilize BRI1 and BAK1 proteins.Thus,our study identifies RLP51 as a positive regulator of BR signaling that enhances the protein levels of BRI1 and BAK1.展开更多
Ursodeoxycholic acid(UDCA)is a naturally occurring,low-toxicity,and hydrophilic bile acid(BA)in the human body that is converted by intestinal flora using primary BA.Solute carrier family 7 member 11(SLC7A11)functions...Ursodeoxycholic acid(UDCA)is a naturally occurring,low-toxicity,and hydrophilic bile acid(BA)in the human body that is converted by intestinal flora using primary BA.Solute carrier family 7 member 11(SLC7A11)functions to uptake extracellular cystine in exchange for glutamate,and is highly expressed in a variety of human cancers.Retroperitoneal liposarcoma(RLPS)refers to liposarcoma originating from the retroperitoneal area.Lipidomics analysis revealed that UDCA was one of the most significantly downregulated metabolites in sera of RLPS patients compared with healthy subjects.The augmentation of UDCA concentration(≥25 mg/mL)demonstrated a suppressive effect on the proliferation of liposarcoma cells.[15N2]-cystine and[13C5]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione(GSH)synthesis.Mechanistically,UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis,leading to reactive oxygen species(ROS)accumulation and mitochondrial oxidative damage.Furthermore,UDCA can promote the anti-cancer effects of ferroptosis inducers(Erastin,RSL3),the murine double minute 2(MDM2)inhibitors(Nutlin 3a,RG7112),cyclin dependent kinase 4(CDK4)inhibitor(Abemaciclib),and glutaminase inhibitor(CB839).Together,UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity,and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA.More importantly,in combination with other antitumor chemotherapy or physiotherapy treatments,UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.展开更多
基金supported by the National Natural Science Foundation of China(32370295 and 32170280 to K.H.)Foundation of Science and Technology of Gansu Province(22ZD6NA049)+3 种基金the Fundamental Research Funds for the Central Universities(lzujbky-2021-kb05 to Y.F.and lzujbky-2023-kb05 to P.L.)the Science and Technology Department of Gansu Province(24JRRA392 to K.H.and 23JRRA1132 to C.X.)China Postdoctoral Science Foundation(2024M751259 and GZB20240285 to B.L.)Science and Technology Program of Gansu Province(25JRRA718 to B.L.).
文摘Brassinosteroids(BRs)are essential phytohormones that broadly regulate plant growth,development,and adaptation to biotic and abiotic stresses.In Arabidopsis,apoplastic BR molecules are perceived by a plasma membrane-localized receptor complex comprising the ligand-binding receptor BRI1 and the co-receptor BAK1.While negative regulators of the BR receptor complex,such as BKI1,BIR3,and PUB12/13,have been well characterized,how BRI1 and BAK1 are positively modulated in the BR pathway remains largely unknown.In this study,a genetic screen involving overexpression of RLP genes in the bak1-3 bkk1-1 double mutant reveals that enhanced RLP51 expression partially suppresses the BR-deficient phenotypes of bak1-3 bkk1-1.RLP51 overexpression also partially rescues the weak bri1 mutant allele,bri1-301.Although the rlp51 single mutant exhibits wild-type-like phenotypes,it enhances BR-defective phenotypes in bri1-301 and bak1 serk1 mutants.RLP51 is next found to interact with both BRI1 and BAK1 without affecting BRI1–BAK1 interaction.Critically,co-expression of RLP51 with BRI1 or BAK1 significantly increases BRI1 and BAK1 protein abundances.RLP51 appears to promote protein synthesis rather than stabilize BRI1 and BAK1 proteins.Thus,our study identifies RLP51 as a positive regulator of BR signaling that enhances the protein levels of BRI1 and BAK1.
基金supported by grants from the National Natural Science Foundation of China(Grant NOs.:82272935,91957120 and 21974114)the Postdoctoral Fellowship Program of CPSF(Program No.:GZC20240901)+5 种基金the Xiamen Medical Industry Combined Guidance Project,China(Project No.:3502Z20244ZD2022)the Scientific Research Foundation for Advanced Talents,Xiang'an Hospital of Xiamen University,China(Grant No.:PM20180917008)the Fundamental Research Funds for the Central Universities,China(Grant No.:20720210001)Major Science and Technology Special Project of Fujian Province,China(Project No.:2022YZ036012)Joint Laboratory of School of Medicine,Xiamen University-Shanghai Jiangxia Blood Technology Co.,Ltd.,China(Grant No.:XDHT2020010C)Joint Research Center of School of Medicine,Xiamen University-Jiangsu Charity Biotech Co.,Ltd.,China(Grant No.:20233160C0002).
文摘Ursodeoxycholic acid(UDCA)is a naturally occurring,low-toxicity,and hydrophilic bile acid(BA)in the human body that is converted by intestinal flora using primary BA.Solute carrier family 7 member 11(SLC7A11)functions to uptake extracellular cystine in exchange for glutamate,and is highly expressed in a variety of human cancers.Retroperitoneal liposarcoma(RLPS)refers to liposarcoma originating from the retroperitoneal area.Lipidomics analysis revealed that UDCA was one of the most significantly downregulated metabolites in sera of RLPS patients compared with healthy subjects.The augmentation of UDCA concentration(≥25 mg/mL)demonstrated a suppressive effect on the proliferation of liposarcoma cells.[15N2]-cystine and[13C5]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione(GSH)synthesis.Mechanistically,UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis,leading to reactive oxygen species(ROS)accumulation and mitochondrial oxidative damage.Furthermore,UDCA can promote the anti-cancer effects of ferroptosis inducers(Erastin,RSL3),the murine double minute 2(MDM2)inhibitors(Nutlin 3a,RG7112),cyclin dependent kinase 4(CDK4)inhibitor(Abemaciclib),and glutaminase inhibitor(CB839).Together,UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity,and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA.More importantly,in combination with other antitumor chemotherapy or physiotherapy treatments,UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.
