Colorectal cancer(CRC)originates from biological events caused by gene mutations in normal intestinal epithelial cells(IECs).Sorting nexin 10(SNX10)is a tumor suppressor in CRC that is involved in regulating chaperone...Colorectal cancer(CRC)originates from biological events caused by gene mutations in normal intestinal epithelial cells(IECs).Sorting nexin 10(SNX10)is a tumor suppressor in CRC that is involved in regulating chaperone-mediated autophagy(CMA)activity,which is implicated in the pathogenesis of CRC and glycolysis process.DEP domain containing 5(DEPDC5)is a negative upstream regulator of mammalian target of rapamycin complex 1(mTORC1).a-hederin has anti-CRC effects.We previously found that SNX10 knockdown in normal human IECs promoted glycolysis and decreased DEPDC5 expression,which was reversed by a-hederin.However,the specific mechanism has not yet been elucidated.Here,we aimed to investigate the specific regulatory mechanism of SNX10 on DEPDC5 expression,and the action of a-hederin on this process.We demonstrated that the degradation of DEPDC5 protein was accelerated after SNX10 knockdown,causing the activation of the mTORC1 pathway,which relied on CMA activation and lysosomal function enhancement.SNX10 interacted with DEPDC5 and recruited it to lysosomes for degradation,and the glycolysis level mediated by mTORC1 was elevated.Additionally,these phenotypes in shSNX10 IECs were compromised by SNX10 rescue.Moreover,a-hederin bound to the SNX10 eDEPDC5 complex and impaired the interaction between SNX10 and DEPDC5,thereby inhibiting CMAmediated DEPDC5 degradation,impairing the aberrant activation of mTORC1 signaling,and eventually reversing the elevation of glycolysis caused by SNX10 knockdown.Overall,we are the first to demonstrate that SNX10-mediated DEPDC5 degradation is a novel strategy for malignant transformation of normal human IECs,with a-hederin regulated during this process.展开更多
The ongoing coronavirus epidemic,including the novel coronavirus(SARS-CoV-2),continues to pose a significant threat to global public health.Host targets address multiple stages of the viral life cycle and provide dive...The ongoing coronavirus epidemic,including the novel coronavirus(SARS-CoV-2),continues to pose a significant threat to global public health.Host targets address multiple stages of the viral life cycle and provide diverse opportunities for therapeutic interventions.This study identified sorting nexin 10(SNX10)as a facilitator of replication of human coronavirus OC43(HCoV-OC43),underscoring its potential as a novel antiviral target.The knockout of SNX10 significantly suppressed HCoV-OC43 replication both in vivo and in vitro.Immunoprecipitation-mass spectrometry(IP-MS)analysis identified the adaptor protein complex 2 subunitμ1(AP2M1)as a direct interactor of SNX10.Specifically,SNX10 facilitates phosphorylation of the AP2M1,thereby enhancing clathrin-mediated viral endocytosis.Furthermore,subsequent binding and internalization assays revealed that SNX10 knockout significantly inhibits viral entry into host cells.Conversely,the reconstitution of SNX10 fully restored viral entry,thereby confirming the critical and indispensable role of SNX10 in pathogen internalization.Simultaneously,SNX10 was identified as a key factor that promotes endosomal acidification by modulating pH levels,which in turn facilitated the release of the viral genome.Notably,the ablation of SNX10 was found to trigger autophagy activation during infection,thereby maintaining intracellular homeostasis.Additionally,it exerted autonomous antiviral effects through lysosomal degradation pathways.Collectively,these findings demonstrate SNX10 serves as a pivotal regulator of the viral life cycle and underscore its therapeutic potential as a multi-faceted antiviral candidate target capable of simultaneously inhibiting viral internalization,viral genomic release,and hostpathogen equilibrium.展开更多
基金supported by the National Natural Science Foundation of China(81973523).
文摘Colorectal cancer(CRC)originates from biological events caused by gene mutations in normal intestinal epithelial cells(IECs).Sorting nexin 10(SNX10)is a tumor suppressor in CRC that is involved in regulating chaperone-mediated autophagy(CMA)activity,which is implicated in the pathogenesis of CRC and glycolysis process.DEP domain containing 5(DEPDC5)is a negative upstream regulator of mammalian target of rapamycin complex 1(mTORC1).a-hederin has anti-CRC effects.We previously found that SNX10 knockdown in normal human IECs promoted glycolysis and decreased DEPDC5 expression,which was reversed by a-hederin.However,the specific mechanism has not yet been elucidated.Here,we aimed to investigate the specific regulatory mechanism of SNX10 on DEPDC5 expression,and the action of a-hederin on this process.We demonstrated that the degradation of DEPDC5 protein was accelerated after SNX10 knockdown,causing the activation of the mTORC1 pathway,which relied on CMA activation and lysosomal function enhancement.SNX10 interacted with DEPDC5 and recruited it to lysosomes for degradation,and the glycolysis level mediated by mTORC1 was elevated.Additionally,these phenotypes in shSNX10 IECs were compromised by SNX10 rescue.Moreover,a-hederin bound to the SNX10 eDEPDC5 complex and impaired the interaction between SNX10 and DEPDC5,thereby inhibiting CMAmediated DEPDC5 degradation,impairing the aberrant activation of mTORC1 signaling,and eventually reversing the elevation of glycolysis caused by SNX10 knockdown.Overall,we are the first to demonstrate that SNX10-mediated DEPDC5 degradation is a novel strategy for malignant transformation of normal human IECs,with a-hederin regulated during this process.
基金supported by the National Natural Science Foundation(82130101)the Major Scientific and Technological Projects of Guangdong Province(2023B1111050008)the Post Scientist Fund awarded by the Chinese Academy of Traditional Chinese Medicine(ZZ13035-02)to Shuwen Liu.Regional Joint Foundation of Basic and Applied Basic Research in Guangdong Province(2023A1515111165)to Chan Yang.
文摘The ongoing coronavirus epidemic,including the novel coronavirus(SARS-CoV-2),continues to pose a significant threat to global public health.Host targets address multiple stages of the viral life cycle and provide diverse opportunities for therapeutic interventions.This study identified sorting nexin 10(SNX10)as a facilitator of replication of human coronavirus OC43(HCoV-OC43),underscoring its potential as a novel antiviral target.The knockout of SNX10 significantly suppressed HCoV-OC43 replication both in vivo and in vitro.Immunoprecipitation-mass spectrometry(IP-MS)analysis identified the adaptor protein complex 2 subunitμ1(AP2M1)as a direct interactor of SNX10.Specifically,SNX10 facilitates phosphorylation of the AP2M1,thereby enhancing clathrin-mediated viral endocytosis.Furthermore,subsequent binding and internalization assays revealed that SNX10 knockout significantly inhibits viral entry into host cells.Conversely,the reconstitution of SNX10 fully restored viral entry,thereby confirming the critical and indispensable role of SNX10 in pathogen internalization.Simultaneously,SNX10 was identified as a key factor that promotes endosomal acidification by modulating pH levels,which in turn facilitated the release of the viral genome.Notably,the ablation of SNX10 was found to trigger autophagy activation during infection,thereby maintaining intracellular homeostasis.Additionally,it exerted autonomous antiviral effects through lysosomal degradation pathways.Collectively,these findings demonstrate SNX10 serves as a pivotal regulator of the viral life cycle and underscore its therapeutic potential as a multi-faceted antiviral candidate target capable of simultaneously inhibiting viral internalization,viral genomic release,and hostpathogen equilibrium.
