Background:Only a few bladder cancer patients benefit from anti-programmed cell death protein 1/programmed cell death ligand 1 immunotherapy.The cluster of differentiation 47(CD47)plays an important role in tumor immu...Background:Only a few bladder cancer patients benefit from anti-programmed cell death protein 1/programmed cell death ligand 1 immunotherapy.The cluster of differentiation 47(CD47)plays an important role in tumor immune evasion.CD47 is a highly glycosylated protein,however,the mechanisms governing CD47 glycosylation and its potential role in immunosuppression are unclear.Therefore,this study aimed to evaluate the function of CD47 glycosylation in bladder cancer.Methods:Western blotting,immunohistochemistry,and flow cytometry were used to measure protein expression,protein-protein interactions,and phagocytosis in bladder cancer.A murine model was employed to investigate the impact of mannosidase alpha class 1B member 1(MAN1B1)modification of CD47 on anti-phagocytosis in vivo.An ex vivo model,patient-derived tumor-like cell clusters,was used to examine the effect of targeting MAN1B1 on phagocytosis.Results:Our research identified that aberrant CD47 glycosylation was responsible for its immunosuppression.The glycosyltransferase MAN1B1 responsible for CD47 glycosylation was highly expressed in bladder cancer.Abnormal activation of extracellular signal-regulated kinase(ERK)was significantly associated with MAN1B1 stability by regulating the interaction between MAN1B1 and the E3 ubiquitin ligase HMG-CoA reductase degradation 1(HRD1).Mechanistically,abnormally activated ERK stabilized MAN1B1,resulting in the glycosylation of CD47 and facilitating immune evasion by enhancing its interaction with signal-regulatory protein alpha(SIRP-α).In vitro and in vivo experiments demonstrated that MAN1B1 knockout weakened CD47-mediated anti-phagocytosis.MAN1B1 inhibitors promoted phagocytosis without causing anemia,offering a safe alternative to anti-CD47 therapy.Conclusions:This comprehensive analysis uncovered that ERK activation stabilizes MAN1B1 by regulating the interaction between MAN1B1 and HRD1,facilitates immune evasion via CD47 glycosylation,and presents new potential targets and strategies for cancer immunotherapy that do not cause anemia.展开更多
In a recent publication in Nature,Zhou and colleagues identified cyclic guanosine monophosphate(cGMP),a canonical phosphodiesterase 5(PDE5)substrate,as a key modulator of dendritic cell(DC)interstitial motility throug...In a recent publication in Nature,Zhou and colleagues identified cyclic guanosine monophosphate(cGMP),a canonical phosphodiesterase 5(PDE5)substrate,as a key modulator of dendritic cell(DC)interstitial motility through Rho kinase(ROCK)-dependent modulation of myosin-II activity.展开更多
This study highlights the role of C-terminal amide-bearing proteins(CTAPs)in protein homeostasis.Researchers discovered that CTAPs,formed under oxidative stress,are selectively recognized and degraded by the E3 ubiqui...This study highlights the role of C-terminal amide-bearing proteins(CTAPs)in protein homeostasis.Researchers discovered that CTAPs,formed under oxidative stress,are selectively recognized and degraded by the E3 ubiquitin ligase FBXO31 to maintain cellular health.Mutations in FBXO31,such as D334N,impair CTAP recognition,leading to abnormal protein accumulation and neurodevelopmental disorders.These findings not only elucidate the mechanism of protein quality control but also suggest potential therapeutic targets for diseases related to oxidative stress and protein misregulation.展开更多
基金the Zhejiang Provincial Natural Science Foundation of China(grant Y24H160082 to Yanlan Yu)the National Natural Science Foundation of China(grant 32000799 to Jie Zhang,grant 81972367 to Yicheng Chen)+1 种基金Zhejiang Province key research and development program(grant 2021C03062 to Guoqing Ding,grant 2023C03010 to Yili Fu)the Zhejiang Provincial Natural Science Foundation of China(grant LQ21H160028 to Fengbin Gao,grant LY23H050004 to HaiyangWu).
文摘Background:Only a few bladder cancer patients benefit from anti-programmed cell death protein 1/programmed cell death ligand 1 immunotherapy.The cluster of differentiation 47(CD47)plays an important role in tumor immune evasion.CD47 is a highly glycosylated protein,however,the mechanisms governing CD47 glycosylation and its potential role in immunosuppression are unclear.Therefore,this study aimed to evaluate the function of CD47 glycosylation in bladder cancer.Methods:Western blotting,immunohistochemistry,and flow cytometry were used to measure protein expression,protein-protein interactions,and phagocytosis in bladder cancer.A murine model was employed to investigate the impact of mannosidase alpha class 1B member 1(MAN1B1)modification of CD47 on anti-phagocytosis in vivo.An ex vivo model,patient-derived tumor-like cell clusters,was used to examine the effect of targeting MAN1B1 on phagocytosis.Results:Our research identified that aberrant CD47 glycosylation was responsible for its immunosuppression.The glycosyltransferase MAN1B1 responsible for CD47 glycosylation was highly expressed in bladder cancer.Abnormal activation of extracellular signal-regulated kinase(ERK)was significantly associated with MAN1B1 stability by regulating the interaction between MAN1B1 and the E3 ubiquitin ligase HMG-CoA reductase degradation 1(HRD1).Mechanistically,abnormally activated ERK stabilized MAN1B1,resulting in the glycosylation of CD47 and facilitating immune evasion by enhancing its interaction with signal-regulatory protein alpha(SIRP-α).In vitro and in vivo experiments demonstrated that MAN1B1 knockout weakened CD47-mediated anti-phagocytosis.MAN1B1 inhibitors promoted phagocytosis without causing anemia,offering a safe alternative to anti-CD47 therapy.Conclusions:This comprehensive analysis uncovered that ERK activation stabilizes MAN1B1 by regulating the interaction between MAN1B1 and HRD1,facilitates immune evasion via CD47 glycosylation,and presents new potential targets and strategies for cancer immunotherapy that do not cause anemia.
基金supported by the National Natural Science Foundation of China(grant number:32000799)Key Research and Development Program of Zhejiang Province(grant number:2025C02058).
文摘In a recent publication in Nature,Zhou and colleagues identified cyclic guanosine monophosphate(cGMP),a canonical phosphodiesterase 5(PDE5)substrate,as a key modulator of dendritic cell(DC)interstitial motility through Rho kinase(ROCK)-dependent modulation of myosin-II activity.
基金supported by the Key Research and Development Program of Zhejiang Province(2025C02058)the National Natural Science Foundation of China(32000799).
文摘This study highlights the role of C-terminal amide-bearing proteins(CTAPs)in protein homeostasis.Researchers discovered that CTAPs,formed under oxidative stress,are selectively recognized and degraded by the E3 ubiquitin ligase FBXO31 to maintain cellular health.Mutations in FBXO31,such as D334N,impair CTAP recognition,leading to abnormal protein accumulation and neurodevelopmental disorders.These findings not only elucidate the mechanism of protein quality control but also suggest potential therapeutic targets for diseases related to oxidative stress and protein misregulation.
