The UFMylation modification is a novel ubiquitin-like conjugation system,consisting of UBA5(E1),UFC1(E2),UFL1(E3),and the conjugating molecule UFM1.Deficiency in this modification leads to embryonic lethality in mice ...The UFMylation modification is a novel ubiquitin-like conjugation system,consisting of UBA5(E1),UFC1(E2),UFL1(E3),and the conjugating molecule UFM1.Deficiency in this modification leads to embryonic lethality in mice and diseases in humans.However,the function of UFL1 is poorly characterized.Studies on Ufl1 conditional knockout mice have demonstrated that the deletion of Ufl1 in cardiomyocytes and in intestinal epithelial cells causes heart failure and increases susceptibility to experimentally induced colitis,respectively,suggesting an essential role of UFL1 in the maintenance of the homeostasis in these organs.Yet,its physiological function in other tissues and organs remains completely unknown.In this study,we generate the nephron tubules specific Ufl1 knockout mice and find that the absence of Ufl1 in renal tubular results in kidney atrophy and interstitial fibrosis.In addition,Ufl1 deficiency causes the activation of unfolded protein response and cell apoptosis,which may be responsible for the kidney atrophy and interstitial fibrosis.Collectively,our results have demonstrated the crucial role of UFL1 in regulating kidney function and maintenance of endoplasmic reticulum homeostasis,providing another layer of understanding kidney atrophy.展开更多
Background and Aims:Sterol regulatory element-binding protein 1(SREBP1),a key regulator of lipogenesis,is highly expressed in tumors,but the mechanisms sustaining its elevated levels remain unclear.The role of UFMylat...Background and Aims:Sterol regulatory element-binding protein 1(SREBP1),a key regulator of lipogenesis,is highly expressed in tumors,but the mechanisms sustaining its elevated levels remain unclear.The role of UFMylation,a posttranslational modification,in modulating SREBP1 stability and tumor progression has not been explored.This study aimed to investigate the role of UFMylation in the progression of liver cancer.Methods:Liquid chromatography-tandem mass spectrometry was employed to investigate the interacting proteins of ubiquitin-fold modifier 1-specific ligase 1(UFL1).Knockdown of UFL1 and DDRGK domain-containing protein 1(DDRGK1)was performed to assess SREBP1 stability.In vitro and in vivo models of hepatocellular carcinoma(HCC)were used to evaluate tumor progression.Clinical correlations between UFL1/DDRGK1 and SREBP1 levels were analyzed in HCC patient samples.Results:SREBP1 undergoes UFMylation,which synergizes with ubiquitination to reduce its stability.Depletion of UFL1 or DDRGK1 increased SREBP1 stability,driving HCC progression.Clinically,UFL1 and DDRGK1 levels were reduced in HCC tissues and inversely correlated with SREBP1 expression.Fatostatin(an SREBP1 inhibitor)enhanced the therapeutic effect of Lenvatinib in HCC models with low UFL1 expression.Conclusions:UFMylation is a critical posttranslational modification that destabilizes SREBP1,and its dysregulation contributes to HCC progression.Targeting the UFMylation-SREBP1 axis,particularly through Fatostatin and Lenvatinib combination therapy,represents a novel therapeutic strategy for HCC.展开更多
基金supported by grants from the National Natural Science Foundation of China(31871416,31730020)the Natural Science Foundation of ZhejiangProvince of China(LY18C070001)the Hangzhou Science and Technology Bureau(20182014B01,20180533B27)。
文摘The UFMylation modification is a novel ubiquitin-like conjugation system,consisting of UBA5(E1),UFC1(E2),UFL1(E3),and the conjugating molecule UFM1.Deficiency in this modification leads to embryonic lethality in mice and diseases in humans.However,the function of UFL1 is poorly characterized.Studies on Ufl1 conditional knockout mice have demonstrated that the deletion of Ufl1 in cardiomyocytes and in intestinal epithelial cells causes heart failure and increases susceptibility to experimentally induced colitis,respectively,suggesting an essential role of UFL1 in the maintenance of the homeostasis in these organs.Yet,its physiological function in other tissues and organs remains completely unknown.In this study,we generate the nephron tubules specific Ufl1 knockout mice and find that the absence of Ufl1 in renal tubular results in kidney atrophy and interstitial fibrosis.In addition,Ufl1 deficiency causes the activation of unfolded protein response and cell apoptosis,which may be responsible for the kidney atrophy and interstitial fibrosis.Collectively,our results have demonstrated the crucial role of UFL1 in regulating kidney function and maintenance of endoplasmic reticulum homeostasis,providing another layer of understanding kidney atrophy.
基金supported by grants from the National Natural Science Foundation of China(82472816 and 82103521 to CZ,82072672 to YY,82472804 to NR)the Natural Science Foundation of Shanghai(25ZR1401061)+1 种基金the Sino-German Mobility Program(M-0603)the Shanghai“Rising Stars of Medical Talents”Youth Development Program(SHWSRS(2024)070).
文摘Background and Aims:Sterol regulatory element-binding protein 1(SREBP1),a key regulator of lipogenesis,is highly expressed in tumors,but the mechanisms sustaining its elevated levels remain unclear.The role of UFMylation,a posttranslational modification,in modulating SREBP1 stability and tumor progression has not been explored.This study aimed to investigate the role of UFMylation in the progression of liver cancer.Methods:Liquid chromatography-tandem mass spectrometry was employed to investigate the interacting proteins of ubiquitin-fold modifier 1-specific ligase 1(UFL1).Knockdown of UFL1 and DDRGK domain-containing protein 1(DDRGK1)was performed to assess SREBP1 stability.In vitro and in vivo models of hepatocellular carcinoma(HCC)were used to evaluate tumor progression.Clinical correlations between UFL1/DDRGK1 and SREBP1 levels were analyzed in HCC patient samples.Results:SREBP1 undergoes UFMylation,which synergizes with ubiquitination to reduce its stability.Depletion of UFL1 or DDRGK1 increased SREBP1 stability,driving HCC progression.Clinically,UFL1 and DDRGK1 levels were reduced in HCC tissues and inversely correlated with SREBP1 expression.Fatostatin(an SREBP1 inhibitor)enhanced the therapeutic effect of Lenvatinib in HCC models with low UFL1 expression.Conclusions:UFMylation is a critical posttranslational modification that destabilizes SREBP1,and its dysregulation contributes to HCC progression.Targeting the UFMylation-SREBP1 axis,particularly through Fatostatin and Lenvatinib combination therapy,represents a novel therapeutic strategy for HCC.
