CD8^(+)T cell immune responses are regulated by multi-layer networks,while the post-translational regulation remains largely unknown.Transmembrane ectodomain shedding is an important post-translational process orchest...CD8^(+)T cell immune responses are regulated by multi-layer networks,while the post-translational regulation remains largely unknown.Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins.Here,by targeting the sheddase A Disintegrin and Metalloprotease(ADAM)17,we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8^(+)T cells.Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8^(+)T cells.T cellspecific deletion of ADAM17 led to a dramatic increase in effector CD8^(+)T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors.Mechanistically,ADAM17 regulated CD8^(+)T cells through cleavage of membrane CD122.ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8^(+)T cells.Intriguingly,inhibition of ADAM17 in CD8^(+)T cells improved the efficacy of chimeric antigen receptor(CAR)T cells in solid tumors.Our findings reveal a critical post-translational regulation in CD8^(+)T cells,providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.展开更多
SEL1L-mediated endoplasmic reticulum-associated degradation(ERAD)plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins.However,it remains unclear how SEL1L regula...SEL1L-mediated endoplasmic reticulum-associated degradation(ERAD)plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins.However,it remains unclear how SEL1L regulates peripheral T-cell survival and homeostasis.Herein,we found that SEL1L deficiency led to a greatly reduced frequency and number of mature T cells,which was further validated by adoptive transfer experiments or bone marrow chimera experiments,accompanied by the induction of multiple forms of cell death.Furthermore,SEL1L deficiency selectively disrupted naïve CD8+T-cell homeostasis,as indicated by the severe loss of the naïve T-cell subset but an increase in the memory T-cell subset.We also found that SEL1L deficiency fueled mTORC1/c-MYC activation and induced a metabolic shift,which was largely attributable to enhanced expression of the IL-15 receptorαandβchains.Mechanistically,single-cell transcriptomic profiling and biochemical analyses further revealed that Sel1l−/−CD8+T cells harbored excessive ER stress,particularly aberrant activation of the PERK-ATF4-CHOP-Bim pathway,which was alleviated by supplementing IL-7 or IL-15.Importantly,PERK inhibition greatly resolved the survival defects of Sel1l−/−CD8+T cells.In addition,IRE1αdeficiency decreased mTORC1 signaling in Sel1l−/−naïve CD8+T cells by downregulating the IL-15 receptorαchain.Altogether,these observations suggest that the ERAD adaptor molecule SEL1L acts as an important checkpoint for preserving the survival and homeostasis of peripheral T cells by regulating the PERK signaling cascade and IL-15 receptor-mediated mTORC1 axis.展开更多
Proteases have a fundamental role in maintaining physiological homeostasis,but their dysregulation results in severe activity imbalance and pathological conditions,including cancer onset,progression,invasion,and metas...Proteases have a fundamental role in maintaining physiological homeostasis,but their dysregulation results in severe activity imbalance and pathological conditions,including cancer onset,progression,invasion,and metastasis.This striking importance plus superior biological recognition and catalytic performance of proteases,combining with the excellent physicochemical characteristics of nanomaterials,results in enzyme-activated nano-drug delivery systems(nanoDDS)that perform theranostic functions in highly specific response to the tumor phenotype stimulus.In the tutorial review,the key advances of protease-responsive nanoDDS in the specific diagnosis and targeted treatment for malignancies are emphatically classified according to the effector biomolecule types,on the premise of summarizing the structure and function of each protease.Subsequently,the incomplete matching and recognition between enzyme and substrate,structural design complexity,volume production,and toxicological issues related to the nanocomposites are highlighted to clarify the direction of efforts in nanotheranostics.This will facilitate the promotion of nanotechnology in the management of malignant tumors.展开更多
基金supported by grants from the National Key Research and Development Program of China 2021YFA1100702(to B.Z.)National Natural Science Foundation of China grants 82271792(to L.S.),32200727(to L.S.)and 82071828(to C.S.)+5 种基金Innovation Capability Support Program of Shaanxi Province 2024CX-GXPT-45(to C.S.)Natural Science Foundation of Shaanxi Province 2017JM8148(to Lin Shi)Fundamental Research Funds for the Central Universities xtr072022002(to B.Z.)the National Natural Science Foundation of China 82350114(to L.Z.)the Natural Science Foundation Outstanding Youth Fund of Jiangsu Province BK20220049(to L.Z.)Suzhou Municipal Key Laboratory SZS2023005(to L.Z.).
文摘CD8^(+)T cell immune responses are regulated by multi-layer networks,while the post-translational regulation remains largely unknown.Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins.Here,by targeting the sheddase A Disintegrin and Metalloprotease(ADAM)17,we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8^(+)T cells.Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8^(+)T cells.T cellspecific deletion of ADAM17 led to a dramatic increase in effector CD8^(+)T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors.Mechanistically,ADAM17 regulated CD8^(+)T cells through cleavage of membrane CD122.ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8^(+)T cells.Intriguingly,inhibition of ADAM17 in CD8^(+)T cells improved the efficacy of chimeric antigen receptor(CAR)T cells in solid tumors.Our findings reveal a critical post-translational regulation in CD8^(+)T cells,providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.
基金supported by the National Key R&D Program of China(2022YFA0807300)the National Natural Science Foundation of China(82271775 and 81971466)+1 种基金the Natural Science Foundation Outstanding Youth Fund of Jiangsu Province(BK20220049)and the CAMS Innovation Fund for Medical Sciences(CIFMS 2021-I2M-1-061,2021-I2M-1-047 and 2022-I2M-2-004).BZ was in part supported by the Innovation Capability Support Program of Shaanxi 2021TD-38.JZ was in part supported by a Translational Research Grant of NCRCH(2020ZKZC04)and the National Natural Science Foundation of China(82071765)supported by the Natural Science Foundation of China(NSFC 31900645).We thank Prof.Yonghong Wan from McMaster University,Canada,for his critical reading of the manuscript and helpful discussions.
文摘SEL1L-mediated endoplasmic reticulum-associated degradation(ERAD)plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins.However,it remains unclear how SEL1L regulates peripheral T-cell survival and homeostasis.Herein,we found that SEL1L deficiency led to a greatly reduced frequency and number of mature T cells,which was further validated by adoptive transfer experiments or bone marrow chimera experiments,accompanied by the induction of multiple forms of cell death.Furthermore,SEL1L deficiency selectively disrupted naïve CD8+T-cell homeostasis,as indicated by the severe loss of the naïve T-cell subset but an increase in the memory T-cell subset.We also found that SEL1L deficiency fueled mTORC1/c-MYC activation and induced a metabolic shift,which was largely attributable to enhanced expression of the IL-15 receptorαandβchains.Mechanistically,single-cell transcriptomic profiling and biochemical analyses further revealed that Sel1l−/−CD8+T cells harbored excessive ER stress,particularly aberrant activation of the PERK-ATF4-CHOP-Bim pathway,which was alleviated by supplementing IL-7 or IL-15.Importantly,PERK inhibition greatly resolved the survival defects of Sel1l−/−CD8+T cells.In addition,IRE1αdeficiency decreased mTORC1 signaling in Sel1l−/−naïve CD8+T cells by downregulating the IL-15 receptorαchain.Altogether,these observations suggest that the ERAD adaptor molecule SEL1L acts as an important checkpoint for preserving the survival and homeostasis of peripheral T cells by regulating the PERK signaling cascade and IL-15 receptor-mediated mTORC1 axis.
基金funded by the National Natural Science Foundation of China(81903662,81860630 and 51903201)China Postdoctoral Science Foundation(2019M661057 and 2019M653660)+2 种基金Natural Science Foundation of Shaanxi Province(2020JQ-086,China)the Natural Science Foundation of Jiangxi(20181BAB205087,China)the Key Project of Jiangxi(20192ACB70012,China)
文摘Proteases have a fundamental role in maintaining physiological homeostasis,but their dysregulation results in severe activity imbalance and pathological conditions,including cancer onset,progression,invasion,and metastasis.This striking importance plus superior biological recognition and catalytic performance of proteases,combining with the excellent physicochemical characteristics of nanomaterials,results in enzyme-activated nano-drug delivery systems(nanoDDS)that perform theranostic functions in highly specific response to the tumor phenotype stimulus.In the tutorial review,the key advances of protease-responsive nanoDDS in the specific diagnosis and targeted treatment for malignancies are emphatically classified according to the effector biomolecule types,on the premise of summarizing the structure and function of each protease.Subsequently,the incomplete matching and recognition between enzyme and substrate,structural design complexity,volume production,and toxicological issues related to the nanocomposites are highlighted to clarify the direction of efforts in nanotheranostics.This will facilitate the promotion of nanotechnology in the management of malignant tumors.
