The degeneration of nerve fibres following injury was first described by Augustus Waller over 170 years ago.Initially assumed to be a passive process,it is now evident that axons respond to insult via regulated cellul...The degeneration of nerve fibres following injury was first described by Augustus Waller over 170 years ago.Initially assumed to be a passive process,it is now evident that axons respond to insult via regulated cellular signaling events resulting in their programmed degeneration.Pro-survival and prodegenerative factors have been identified and their regulato ry mechanisms are beginning to emerge.The ubiquitin system has been implicated in the pro-degenerative process and a key component is the ubiquitin E3 ligase MYCBP2(also known as PHR1).Ubiquitin E3 ligases are tasked with the transfer of the small protein modifier ubiquitin to substrates and consist of hundreds of members.They can be classified as single subunit systems or as multi-subunit complexes.Their catalytic domains can also be assigned to three general architectures.Hints that MYCBP2 might not conform to these established formats came to light and it is now clear from biochemical and structural studies that MYCBP2 is indeed an outlier in terms of its modus operandi.Furthermore,the unconventional way in which MYCBP2 transfe rs ubiquitin to substrates has been linked to neurodevelopmental and pro-degenerative function.Herein,we will summarize these research developments relating to the unusual features of MYCBP2 and postulate therapeutic strategies that prevent Walle rian degeneration.These have exciting potential for providing relief from pathological neuropathies and neurodegenerative diseases.展开更多
Obesity is a major pathological factor that induces insulin resistance and consequent type 2 diabetes through multiple mechanisms.Inactivation of the insulin receptor(INSR)contributes to the development of insulin res...Obesity is a major pathological factor that induces insulin resistance and consequent type 2 diabetes through multiple mechanisms.Inactivation of the insulin receptor(INSR)contributes to the development of insulin resistance,whose protein level is down-regulated in obesity through as yet-undefined mechanisms.Here we show that the E3-ligase TRAF6 is a critical regulator of INSR maturation,whose inactivation prevents palmitic acid-or high-fat diet-induced diminution of the INSR.Consequently,genetic inactivation of TRAF6 enhances insulin signaling that further increases muscle glucose uptake and inhibits hepatic gluconeogenesis.TRAF6 inactivation increases the proprotein convertase FURIN that controls the processing of pro-INSR to mature INSR.Mechanistically,TRAF6 associates with the Golgi apparatus,where it ubiquitinates the cytosolic tail of FURIN,leading to its lysosomal degradation.This TRAF6-FURIN axis also regulates cholesterol metabolism via PCSK9 processing in the circulation.Collectively,our results reveal a critical role of TRAF6 in regulating proprotein processing and have therapeutic implications for metabolic control.展开更多
Intermittent fasting(IF)is a convenient dietary intervention for multiple diseases,including type 2 diabetes.However,whether it can be used as a long-term antidiabetic approach is still unknown.Here,we confirm that IF...Intermittent fasting(IF)is a convenient dietary intervention for multiple diseases,including type 2 diabetes.However,whether it can be used as a long-term antidiabetic approach is still unknown.Here,we confirm that IF alone is beneficial for both moderate and severe diabetic mice,but its antidiabetic effects clearly diminish at later stages,especially for severe diabetic db/db mice,which have obviously impaired autophagy.We found that static magnetic fields can directly promote actin assembly and boost IF-induced autophagy.Consequently,the pancreatic islet and liver were improved,and the antidiabetic effects of IF were boosted.In fact,at later stages,combined static magnetic field and IF could reduce the blood glucose level of moderate type 2 diabetic mice by 40.5%(P<0.001)and severe type 2 diabetes by 34.4%(P<0.05),when IF alone no longer has significant blood glucose reduction effects.Therefore,although IF is generally beneficial for diabetes,our data reveal its insufficiency for late-stage diabetes,which can be compensated by a simple,noninvasive,long-lasting,and nonpharmacological strategy for effective long-term diabetic control.展开更多
In the Research Article“Enhanced effects of intermittent fasting by magnetic fields in severe diabetes”,an error was inadvertently introduced during the production process[1].The unit of measurement in Fig.iB is“KG...In the Research Article“Enhanced effects of intermittent fasting by magnetic fields in severe diabetes”,an error was inadvertently introduced during the production process[1].The unit of measurement in Fig.iB is“KGs”,not“kg”The publisher apologizes for this error,which is corrected in the figure below.展开更多
基金the United Kingdom MRC(MC_UU_12016/8)the Biotechnology and Biological Sciences Research Council(BB/P003982/1)The Michael J.Fox Foundation(to SV)。
文摘The degeneration of nerve fibres following injury was first described by Augustus Waller over 170 years ago.Initially assumed to be a passive process,it is now evident that axons respond to insult via regulated cellular signaling events resulting in their programmed degeneration.Pro-survival and prodegenerative factors have been identified and their regulato ry mechanisms are beginning to emerge.The ubiquitin system has been implicated in the pro-degenerative process and a key component is the ubiquitin E3 ligase MYCBP2(also known as PHR1).Ubiquitin E3 ligases are tasked with the transfer of the small protein modifier ubiquitin to substrates and consist of hundreds of members.They can be classified as single subunit systems or as multi-subunit complexes.Their catalytic domains can also be assigned to three general architectures.Hints that MYCBP2 might not conform to these established formats came to light and it is now clear from biochemical and structural studies that MYCBP2 is indeed an outlier in terms of its modus operandi.Furthermore,the unconventional way in which MYCBP2 transfe rs ubiquitin to substrates has been linked to neurodevelopmental and pro-degenerative function.Herein,we will summarize these research developments relating to the unusual features of MYCBP2 and postulate therapeutic strategies that prevent Walle rian degeneration.These have exciting potential for providing relief from pathological neuropathies and neurodegenerative diseases.
基金supported by the National Natural Science Foundation of China(32025019)the Ministry of Science and Technology of China(2021YFF0702100,2018YFA0801100)+2 种基金the Science and Technology Foundation of Jiangsu Province of China(BK20243041)the Fundamental Research Funds for the Central Universities(021414380533)Wellcome Trust Investigator Award(209380/Z/17/Z).
文摘Obesity is a major pathological factor that induces insulin resistance and consequent type 2 diabetes through multiple mechanisms.Inactivation of the insulin receptor(INSR)contributes to the development of insulin resistance,whose protein level is down-regulated in obesity through as yet-undefined mechanisms.Here we show that the E3-ligase TRAF6 is a critical regulator of INSR maturation,whose inactivation prevents palmitic acid-or high-fat diet-induced diminution of the INSR.Consequently,genetic inactivation of TRAF6 enhances insulin signaling that further increases muscle glucose uptake and inhibits hepatic gluconeogenesis.TRAF6 inactivation increases the proprotein convertase FURIN that controls the processing of pro-INSR to mature INSR.Mechanistically,TRAF6 associates with the Golgi apparatus,where it ubiquitinates the cytosolic tail of FURIN,leading to its lysosomal degradation.This TRAF6-FURIN axis also regulates cholesterol metabolism via PCSK9 processing in the circulation.Collectively,our results reveal a critical role of TRAF6 in regulating proprotein processing and have therapeutic implications for metabolic control.
基金supported by National Key R&D Program of China(2023YFB3507004)National Natural Science Foundation of China(U21A20148 and 52377228)+4 种基金International Partnership Program of Chinese Academy of Sciences(116134-KYSB20210052)Heye Health Technology Chong Ming Project(HYCMP2021010)CASHIPS Director's Fund(BJPY2021A06)Collaborative Innovation Program of Hefei Science Center,CAS(2022HSC-CIP002)CAS Project for Young Scientists in Basic Research(YSBR-097).
文摘Intermittent fasting(IF)is a convenient dietary intervention for multiple diseases,including type 2 diabetes.However,whether it can be used as a long-term antidiabetic approach is still unknown.Here,we confirm that IF alone is beneficial for both moderate and severe diabetic mice,but its antidiabetic effects clearly diminish at later stages,especially for severe diabetic db/db mice,which have obviously impaired autophagy.We found that static magnetic fields can directly promote actin assembly and boost IF-induced autophagy.Consequently,the pancreatic islet and liver were improved,and the antidiabetic effects of IF were boosted.In fact,at later stages,combined static magnetic field and IF could reduce the blood glucose level of moderate type 2 diabetic mice by 40.5%(P<0.001)and severe type 2 diabetes by 34.4%(P<0.05),when IF alone no longer has significant blood glucose reduction effects.Therefore,although IF is generally beneficial for diabetes,our data reveal its insufficiency for late-stage diabetes,which can be compensated by a simple,noninvasive,long-lasting,and nonpharmacological strategy for effective long-term diabetic control.
文摘In the Research Article“Enhanced effects of intermittent fasting by magnetic fields in severe diabetes”,an error was inadvertently introduced during the production process[1].The unit of measurement in Fig.iB is“KGs”,not“kg”The publisher apologizes for this error,which is corrected in the figure below.
