Protein-metabolite interactions(PMIs)play important roles in various biological processes,especially in disease progression.However,due to the complexity of living cells,it is very difficult to identify specific PMIs....Protein-metabolite interactions(PMIs)play important roles in various biological processes,especially in disease progression.However,due to the complexity of living cells,it is very difficult to identify specific PMIs.Herein,we chose one oncogenic factor,metadherin(MTDH),as a bait to identify its in vivo interacting metabolites in cancer cells.Cholesterol is an important metabolite and essential structural component of cell membranes.It could also drive several diseases including cancer.Interestingly,we found that cholesterol robustly interacted with MTDH and downregulated the expression of MTDH in cancer cells.Furthermore,MTDH disturbed metabolite alterations under cholesterol treatment in MTDH transduced cancer cells.Collectively,our results uncover an undescribed PMI where MTDH,as an oncogenic factor,might positively regulate cancer progression by interacting with choleste rol.This study interprets the theoretical basis of PMI-oriented cancer progression and targeting therapies in clinic.展开更多
Pyruvate is an essential fuel for maintaining the tricarboxylic acid(TCA)cycle in the mitochondria.However,the precise mole-cular mechanism of pyruvate uptake by mitochondrial pyruvate carrier(MPC)is largely unknown.H...Pyruvate is an essential fuel for maintaining the tricarboxylic acid(TCA)cycle in the mitochondria.However,the precise mole-cular mechanism of pyruvate uptake by mitochondrial pyruvate carrier(MPC)is largely unknown.Here,we report that the DNA/RNA-binding protein Y-box binding protein 1(YBX1)is localized to the mitochondrial inter-membrane space by its C-terminal domain(CTD)in cancer cells.In mitochondria,YBX1 inhibits pyruvate uptake by associating with MPC1/2,thereby suppressing pyruvate-dependent TCA cycle flux.This association,in turn,promotes MPC-mediated glutaminolysis and histone lactylation.Our findings reveal that the YBX1-MPC axis exhibits a positive correlation with metastatic potential,while does not affect cell proliferation in both cultured cells and tumor xenografts.Therefore,the restricted pyruvate uptake into mitochondria potentially represents a hallmark of metastatic capacity,suggesting that the YBX1-MPC axis is a therapeutic target for combating cancer metastasis.展开更多
基金the National Natural Science Foundation of China(Nos.81672440,21575142)Innovation Program of Science and Research from the DICP,CAS(No.DICP ZZBS201803)。
文摘Protein-metabolite interactions(PMIs)play important roles in various biological processes,especially in disease progression.However,due to the complexity of living cells,it is very difficult to identify specific PMIs.Herein,we chose one oncogenic factor,metadherin(MTDH),as a bait to identify its in vivo interacting metabolites in cancer cells.Cholesterol is an important metabolite and essential structural component of cell membranes.It could also drive several diseases including cancer.Interestingly,we found that cholesterol robustly interacted with MTDH and downregulated the expression of MTDH in cancer cells.Furthermore,MTDH disturbed metabolite alterations under cholesterol treatment in MTDH transduced cancer cells.Collectively,our results uncover an undescribed PMI where MTDH,as an oncogenic factor,might positively regulate cancer progression by interacting with choleste rol.This study interprets the theoretical basis of PMI-oriented cancer progression and targeting therapies in clinic.
基金This study was supported by the National Key Research and Development Program of China(2022YFA0806503)grants from the National Natural Science Foundation of China(No.81972625,No.21907093)+1 种基金Dalian Science and Technology Innovation Funding(2019J12SN52)Liaoning Revitalization Talents Program(XLYC2002035).
文摘Pyruvate is an essential fuel for maintaining the tricarboxylic acid(TCA)cycle in the mitochondria.However,the precise mole-cular mechanism of pyruvate uptake by mitochondrial pyruvate carrier(MPC)is largely unknown.Here,we report that the DNA/RNA-binding protein Y-box binding protein 1(YBX1)is localized to the mitochondrial inter-membrane space by its C-terminal domain(CTD)in cancer cells.In mitochondria,YBX1 inhibits pyruvate uptake by associating with MPC1/2,thereby suppressing pyruvate-dependent TCA cycle flux.This association,in turn,promotes MPC-mediated glutaminolysis and histone lactylation.Our findings reveal that the YBX1-MPC axis exhibits a positive correlation with metastatic potential,while does not affect cell proliferation in both cultured cells and tumor xenografts.Therefore,the restricted pyruvate uptake into mitochondria potentially represents a hallmark of metastatic capacity,suggesting that the YBX1-MPC axis is a therapeutic target for combating cancer metastasis.
