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
Immune checkpoint blockade(ICB)therapy,which has revolutionized cancer treatment,has been approved for the treatment of triple-negative breast cancer(TNBC).Unfortunately,most patients with TNBC are either not eligible...Immune checkpoint blockade(ICB)therapy,which has revolutionized cancer treatment,has been approved for the treatment of triple-negative breast cancer(TNBC).Unfortunately,most patients with TNBC are either not eligible for treatment or exhibit resistance,resulting in limited overall survival benefits.There is an urgent need to elucidate the mechanisms of resistance and enhance therapeutic efficacy.Here,via CRISPR activation(CRISPRa)screening,we identified family with sequence similarity 114 member A1(FAM114A1)as a key mediator of immune evasion and ICB resistance in TNBC.Mechanistically,FAM114A1 binds p85αto disrupt the p85α/p110αprotein complex,thus activating the PI3K/AKT pathway and simultaneously preventing condensate formation of E2F Transcription Factor 4(E2F4)to promote E2F4-driven Metadherin(MTDH)transcription.Upregulation of these FAM114A1-mediated pathways suppresses tumor antigen presentation and consequently attenuates antitumor immunity in TNBC.Moreover,targeting FAM114A1 improves the therapeutic effectiveness of anti-PD-1 therapy in mouse models,and a FAM114A1-based signature shows strong predictive performance for identifying patients with TNBC who may benefit from ICB.Collectively,our findings not only reveal that FAM114A1 is an immune evasion driver but also highlight it as a promising biomarker and therapeutic target.Our study provides new insights into TNBC immune evasion and outlines a potential avenue to improve the effectiveness of ICB.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(2021hwyq55 and 82472950 to M.Shen,32270745 to Y.Lu)the Natural Science Foundation of Shanghai(23ZR1466500 to Y.Lu)+1 种基金the Shanghai Municipal Health Commission(2022YQ067 to Y.Lu)supported by the Human Phenome Data Center of Fudan University。
文摘Immune checkpoint blockade(ICB)therapy,which has revolutionized cancer treatment,has been approved for the treatment of triple-negative breast cancer(TNBC).Unfortunately,most patients with TNBC are either not eligible for treatment or exhibit resistance,resulting in limited overall survival benefits.There is an urgent need to elucidate the mechanisms of resistance and enhance therapeutic efficacy.Here,via CRISPR activation(CRISPRa)screening,we identified family with sequence similarity 114 member A1(FAM114A1)as a key mediator of immune evasion and ICB resistance in TNBC.Mechanistically,FAM114A1 binds p85αto disrupt the p85α/p110αprotein complex,thus activating the PI3K/AKT pathway and simultaneously preventing condensate formation of E2F Transcription Factor 4(E2F4)to promote E2F4-driven Metadherin(MTDH)transcription.Upregulation of these FAM114A1-mediated pathways suppresses tumor antigen presentation and consequently attenuates antitumor immunity in TNBC.Moreover,targeting FAM114A1 improves the therapeutic effectiveness of anti-PD-1 therapy in mouse models,and a FAM114A1-based signature shows strong predictive performance for identifying patients with TNBC who may benefit from ICB.Collectively,our findings not only reveal that FAM114A1 is an immune evasion driver but also highlight it as a promising biomarker and therapeutic target.Our study provides new insights into TNBC immune evasion and outlines a potential avenue to improve the effectiveness of ICB.
