The well-known insulin-like growth factor 1(IGF1)/IGF-1 receptor(IGF-1R)signaling pathway is overexpressed in many tumors,and is thus an attractive target for cancer treatment.However,results have often been disappoin...The well-known insulin-like growth factor 1(IGF1)/IGF-1 receptor(IGF-1R)signaling pathway is overexpressed in many tumors,and is thus an attractive target for cancer treatment.However,results have often been disappointing due to crosstalk with other signals.Here,we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma(HCC)cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2(SERCA2)activity.In response to ligand binding,IGF-1Rβis translocated into the ER byβ-arrestin2(β-arr2).Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rβ.SERCA2 activity is heavily dependent on the increase in ER IGF-1Rβlevels.ER IGF-1Rβphosphorylates SERCA2 on Tyr^(990)to enhance its activity.Mutation of SERCA2-Tyr^(990)disrupted the interaction of ER IGF-1Rβwith SERCA2,and therefore ER IGF-1Rβfailed to promote SERCA2 activity.The enhancement of SERCA2 activity triggered Ca_(ER)^(2+)perturbation,leading to an increase in autophagy.Thapsigargin blocked the interaction between SERCA2and ER IGF-1Rβand therefore SERCA2 activity,resulting in inhibition of HCC growth.In conclusion,the translocation of IGF-1R into the ER triggers Ca_(ER)^(2+)perturbation by enhancing SERCA2 activity through phosphorylating Tyr^(990)in HCC.展开更多
Ischemic heart failure(HF)remains a leading cause of morbidity and mortality.Maintaining homeostasis of cardiac function and preventing cardiac remodeling deterioration are critical to halting HF progression.Methyltra...Ischemic heart failure(HF)remains a leading cause of morbidity and mortality.Maintaining homeostasis of cardiac function and preventing cardiac remodeling deterioration are critical to halting HF progression.Methyltransferase-like protein 13(Mettl13)has been shown to regulate protein translation efficiency by acting as a protein lysine methyltransferase,but its role in cardiac pathology remains unexplored.This study aims to characterize the roles and mechanisms of Mettl13 in cardiac contractile function and HF.We found that Mettl13 was downregulated in the failing hearts of mice post-myocardial infarction(MI)and in a cellular model of oxidative stress.Cardiomyocyte-specific overexpression of Mettl13 mediated by AAV9-Mettl13 attenuated cardiac contractile dysfunction and fibrosis in response to MI,while silencing of Mettl13 impaired cardiac function in normal mice.Moreover,Mettl13 overexpression abrogated the reduction in cell shortening,Ca^(2+)transient amplitude and SERCA2a protein levels in the cardiomyocytes of adult mice with MI.Conversely,knockdown of Mettl13 impaired the contractility of cardiomyocytes,and decreased Ca^(2+)transient amplitude and SERCA2a protein expression in vivo and in vitro.Mechanistically,Mettl13 impaired the stability of c-Cbl by inducing lysine methylation of c-Cbl,which in turn inhibited ubiquitination-dependent degradation of SERCA2a.Furthermore,the inhibitory effects of knocking down Mettl13 on SERCA2a protein expression and Ca^(2+)transients were partially rescued by silencing c-Cbl in H_(2)O_(2)-treated cardiomyocytes.In conclusion,our study uncovers a novel mechanism that involves the Mettl13/c-Cbl/SERCA2a axis in regulating cardiac contractile function and remodeling,and identifies Mettl13 as a novel therapeutic target for ischemic HF.展开更多
Chemoresistance remains a major obstacle to successful treatment of triple negative breast cancer(TNBC).Identification of druggable vulnerabilities is an important aim for TNBC therapy.Here,we report that SERCA2 expre...Chemoresistance remains a major obstacle to successful treatment of triple negative breast cancer(TNBC).Identification of druggable vulnerabilities is an important aim for TNBC therapy.Here,we report that SERCA2 expression correlates with TNBC progression in human patients,which promotes TNBC cell proliferation,migration and chemoresistance.Mechanistically,SERCA2 interacts with LC3B via LIR motif,facilitating WIPI2-independent autophagosome formation to induce autophagy.Autophagy-mediated SERCA2 degradation induces SERCA2 transactivation through a Ca^(2+)/CaMKK/CREB-1 feedback.Moreover,we found that SERCA2-targeting small molecule RL71 enhances SERCA2-LC3B interaction and induces excessive autophagic cell death.The increase in SERCA2 expression predisposes TNBC cells to RL71-induced autophagic cell death in vitro and in vivo.This study elucidates a mechanism by which TNBC cells maintain their high autophagy activity to induce chemoresistance,and suggests increased SERCA2 expression as a druggable vulnerability for TNBC.展开更多
基金supported by the National Natural Science Foundation of China(81973350,China)supported by the National Natural Science Foundation of China(81872884 and 82173841,China)Beijing Natural Science Foundation(7222253,China)。
文摘The well-known insulin-like growth factor 1(IGF1)/IGF-1 receptor(IGF-1R)signaling pathway is overexpressed in many tumors,and is thus an attractive target for cancer treatment.However,results have often been disappointing due to crosstalk with other signals.Here,we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma(HCC)cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2(SERCA2)activity.In response to ligand binding,IGF-1Rβis translocated into the ER byβ-arrestin2(β-arr2).Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rβ.SERCA2 activity is heavily dependent on the increase in ER IGF-1Rβlevels.ER IGF-1Rβphosphorylates SERCA2 on Tyr^(990)to enhance its activity.Mutation of SERCA2-Tyr^(990)disrupted the interaction of ER IGF-1Rβwith SERCA2,and therefore ER IGF-1Rβfailed to promote SERCA2 activity.The enhancement of SERCA2 activity triggered Ca_(ER)^(2+)perturbation,leading to an increase in autophagy.Thapsigargin blocked the interaction between SERCA2and ER IGF-1Rβand therefore SERCA2 activity,resulting in inhibition of HCC growth.In conclusion,the translocation of IGF-1R into the ER triggers Ca_(ER)^(2+)perturbation by enhancing SERCA2 activity through phosphorylating Tyr^(990)in HCC.
基金supported by the National Natural Science Foundation of China (82273928,U21A20339)the Outstanding Youth Project of Natural Science Foundation of Heilongjiang Province (YQ2020H010)+2 种基金Youth Project of Scientific Research Institution of Heilongjiang Province (CZKYF2023-1-C047)CAMS Innovation Fund for Medical Sciences (CIFMS) (2019-I2M-5-078)Harbin Medical University Youth Talents Start-up Funding (2019-YQ-03)。
文摘Ischemic heart failure(HF)remains a leading cause of morbidity and mortality.Maintaining homeostasis of cardiac function and preventing cardiac remodeling deterioration are critical to halting HF progression.Methyltransferase-like protein 13(Mettl13)has been shown to regulate protein translation efficiency by acting as a protein lysine methyltransferase,but its role in cardiac pathology remains unexplored.This study aims to characterize the roles and mechanisms of Mettl13 in cardiac contractile function and HF.We found that Mettl13 was downregulated in the failing hearts of mice post-myocardial infarction(MI)and in a cellular model of oxidative stress.Cardiomyocyte-specific overexpression of Mettl13 mediated by AAV9-Mettl13 attenuated cardiac contractile dysfunction and fibrosis in response to MI,while silencing of Mettl13 impaired cardiac function in normal mice.Moreover,Mettl13 overexpression abrogated the reduction in cell shortening,Ca^(2+)transient amplitude and SERCA2a protein levels in the cardiomyocytes of adult mice with MI.Conversely,knockdown of Mettl13 impaired the contractility of cardiomyocytes,and decreased Ca^(2+)transient amplitude and SERCA2a protein expression in vivo and in vitro.Mechanistically,Mettl13 impaired the stability of c-Cbl by inducing lysine methylation of c-Cbl,which in turn inhibited ubiquitination-dependent degradation of SERCA2a.Furthermore,the inhibitory effects of knocking down Mettl13 on SERCA2a protein expression and Ca^(2+)transients were partially rescued by silencing c-Cbl in H_(2)O_(2)-treated cardiomyocytes.In conclusion,our study uncovers a novel mechanism that involves the Mettl13/c-Cbl/SERCA2a axis in regulating cardiac contractile function and remodeling,and identifies Mettl13 as a novel therapeutic target for ischemic HF.
基金This study was funded by National Natural Science Foundation of China(Nos.21937005 and 81974504)Natural Science Foundation of Jiangsu Province(No.BK 20191251,China)+1 种基金the Fundamental Research Funds for the Central Universities(China)National Key R&D·Program of China(No.2017YFA0506000).
文摘Chemoresistance remains a major obstacle to successful treatment of triple negative breast cancer(TNBC).Identification of druggable vulnerabilities is an important aim for TNBC therapy.Here,we report that SERCA2 expression correlates with TNBC progression in human patients,which promotes TNBC cell proliferation,migration and chemoresistance.Mechanistically,SERCA2 interacts with LC3B via LIR motif,facilitating WIPI2-independent autophagosome formation to induce autophagy.Autophagy-mediated SERCA2 degradation induces SERCA2 transactivation through a Ca^(2+)/CaMKK/CREB-1 feedback.Moreover,we found that SERCA2-targeting small molecule RL71 enhances SERCA2-LC3B interaction and induces excessive autophagic cell death.The increase in SERCA2 expression predisposes TNBC cells to RL71-induced autophagic cell death in vitro and in vivo.This study elucidates a mechanism by which TNBC cells maintain their high autophagy activity to induce chemoresistance,and suggests increased SERCA2 expression as a druggable vulnerability for TNBC.
