Parkinson's disease(PD)is the most common neurodegenerative movement disease.It is featured by abnormal alphα-synuclein(α-syn)aggregation in dopaminergic neurons in the substantia nigra.Macroautophagy(autophagy)...Parkinson's disease(PD)is the most common neurodegenerative movement disease.It is featured by abnormal alphα-synuclein(α-syn)aggregation in dopaminergic neurons in the substantia nigra.Macroautophagy(autophagy)is an evolutionarily conserved cellular process for degradation of cellular contents,including protein aggregates,to maintain cellular homeostasis.Corynoxine B(Cory B),a natural alkaloid isolated from Uncaria rhynchophylla(Miq.)Jacks.,has been reported to promote the clearance ofα-syn in cell models by inducing autophagy.However,the molecular mechanism by which Cory B induces autophagy is not known,and theα-syn-lowering activity of Cory B has not been verified in animal models.Here,we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2.Depletion of HMGB1/2 impaired Cory B-induced autophagy.We showed for the first time that,similar to HMGB1,HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinaseⅢactivity both under basal and stimulated conditions.By applying cellular thermal shift assay,surface plasmon resonance,and molecular docking,we confirmed that Cory B directly binds to HMGB1/2 near the C106 site.Furthermore,in vivo studies with a wild-typeα-syn transgenic drosophila model of PD and an A53Tα-syn transgenic mouse model of PD,Cory B enhanced autophagy,promotedα-syn clearance and improved behavioral abnormalities.Taken together,the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinaseⅢactivity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.展开更多
AbstracBteclin-1 is the firstly-identified mammalian protein of the autophagy machinery,which functions as a molecular scaffold for the assembly of PI3KC3(class II phosphatidylinositol 3 kinase)complex,thus controllin...AbstracBteclin-1 is the firstly-identified mammalian protein of the autophagy machinery,which functions as a molecular scaffold for the assembly of PI3KC3(class II phosphatidylinositol 3 kinase)complex,thus controlling autophagy induction and other cellular trafficking events.Notably,there is mounting evidence establishing the implications of Beclin-1 in diverse tumorigenesis processes,including tumor suppression and progression as well as resistance to cancer therapeutics and CSC(cancer stem-like cell)maintenance.More importantly,Beclin-1 has been confirmed as a potential target for the treatment of multiple cancers.In this review,we provide a comprehensive survey of the structure,functions,and regulations of Beclin-1,and we discuss recent advances in understanding the controversial roles of Beclin-1 in oncology.Moreover,we focus on summarizing the targeted Beclin-1-regulating strategies in cancer therapy,providing novel insights into a promising strategy for regulating Beclin-1 to improvecancer therapeutics in thefuture.展开更多
基金supported by the National Natural Science Foundation of China(No.82271455)the Guangdong Basic and Applied Basic Research Foundation(No.2022A1515012416,China)+5 种基金the Science and Technology Development Fund,Macao SAR(No.0128/2019/A3,China)the Shenzhen Fundamental Research Program(No.SGDX20210823103804030,China)the University of Macao grants(No.MYRG2022-00094-ICMS,China)awarded to Jia-hong Lupartly supported by Hong Kong Health and Medical Research Fund(HMRF/17182551,HMRF/09203776,China)the Hong Kong General Research Fund(HKBU 12100618,HKBU 12101022,China)from Hong Kong Governmentthe Research Fund from Hong Kong Baptist University(HKBU/RC-IRCs/17-18/03,IRCMS/19-20/H02,China)awarded to Min Li。
文摘Parkinson's disease(PD)is the most common neurodegenerative movement disease.It is featured by abnormal alphα-synuclein(α-syn)aggregation in dopaminergic neurons in the substantia nigra.Macroautophagy(autophagy)is an evolutionarily conserved cellular process for degradation of cellular contents,including protein aggregates,to maintain cellular homeostasis.Corynoxine B(Cory B),a natural alkaloid isolated from Uncaria rhynchophylla(Miq.)Jacks.,has been reported to promote the clearance ofα-syn in cell models by inducing autophagy.However,the molecular mechanism by which Cory B induces autophagy is not known,and theα-syn-lowering activity of Cory B has not been verified in animal models.Here,we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2.Depletion of HMGB1/2 impaired Cory B-induced autophagy.We showed for the first time that,similar to HMGB1,HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinaseⅢactivity both under basal and stimulated conditions.By applying cellular thermal shift assay,surface plasmon resonance,and molecular docking,we confirmed that Cory B directly binds to HMGB1/2 near the C106 site.Furthermore,in vivo studies with a wild-typeα-syn transgenic drosophila model of PD and an A53Tα-syn transgenic mouse model of PD,Cory B enhanced autophagy,promotedα-syn clearance and improved behavioral abnormalities.Taken together,the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinaseⅢactivity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.
基金supported by the National Natural Science Foundation of China(Grant Nos.22177084 and 82173666)Sichuan Science and Technology Program(Grant No.2022YFQ0054,China)the Open Research Fund of Chengdu University of Traditional Chinese Medicine State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China.
文摘AbstracBteclin-1 is the firstly-identified mammalian protein of the autophagy machinery,which functions as a molecular scaffold for the assembly of PI3KC3(class II phosphatidylinositol 3 kinase)complex,thus controlling autophagy induction and other cellular trafficking events.Notably,there is mounting evidence establishing the implications of Beclin-1 in diverse tumorigenesis processes,including tumor suppression and progression as well as resistance to cancer therapeutics and CSC(cancer stem-like cell)maintenance.More importantly,Beclin-1 has been confirmed as a potential target for the treatment of multiple cancers.In this review,we provide a comprehensive survey of the structure,functions,and regulations of Beclin-1,and we discuss recent advances in understanding the controversial roles of Beclin-1 in oncology.Moreover,we focus on summarizing the targeted Beclin-1-regulating strategies in cancer therapy,providing novel insights into a promising strategy for regulating Beclin-1 to improvecancer therapeutics in thefuture.
