O-GlcNAcylation is a post-translational modification that serves as a cellular nutrient sensor and participates in multiple physiological and pathological processes.However,it remains uncertain whether O-GlcNAcylation...O-GlcNAcylation is a post-translational modification that serves as a cellular nutrient sensor and participates in multiple physiological and pathological processes.However,it remains uncertain whether O-GlcNAcylation is involved in the regulation of phagocytosis.Here,we demonstrate a rapid increase in protein OGlcNAcylation in response to phagocytotic stimuli.Knockout of the O-GlcNAc transferase or pharmacological inhibition of O-GlcNAcylation dramatically blocks phagocytosis,resulting in the disruption of retinal structure and function.Mechanistic studies reveal that the O-GlcNAc transferase interacts with Ezrin,a membrane-cytoskeleton linker protein,to catalyze its O-GlcNAcylation.Our data further show that Ezrin OGlcNAcylation promotes its localization to the cell cortex,thereby stimulating the membrane-cytoskeleton interaction needed for efficient phagocytosis.These findings identify a previously unrecognized role for protein O-GlcNAcylation in phagocytosis with important implications in both health and diseases.展开更多
Carbohydrate metabolism disorders(CMDs),such as diabetes,galactosemia,and mannosidosis,cause ciliopathy-like multiorgan defects.However,the mechanistic link of cilia to CMD complications is still poorly understood.Her...Carbohydrate metabolism disorders(CMDs),such as diabetes,galactosemia,and mannosidosis,cause ciliopathy-like multiorgan defects.However,the mechanistic link of cilia to CMD complications is still poorly understood.Herein,we describe significant cilium disassembly upon treatment of cells with pathologically relevant aldoses rather than the corresponding sugar alcohols.Moreover,environmental aldehydes are able to trigger cilium disassembly by the steric hindrance effect of their formyl groups.Mechanistic studies reveal that aldehydes stimulate extracellular calcium influx across the plasma membrane,which subsequently activates the calmodulin-Aurora A-histone deacetylase 6 pathway to deacetylate axonemal microtubules and triggers cilium disassembly.In vivo experiments further show that Hdac6 knockout mice are resistant to aldehyde-induced disassembly of tracheal cilia and sperm flagella.These findings reveal a previously unrecognized role for formyl group-mediated cilium disassembly in the complications of CMDs.展开更多
基金supported by grants from the National Natural Science Foundation of China (32100549 and 31991193)
文摘O-GlcNAcylation is a post-translational modification that serves as a cellular nutrient sensor and participates in multiple physiological and pathological processes.However,it remains uncertain whether O-GlcNAcylation is involved in the regulation of phagocytosis.Here,we demonstrate a rapid increase in protein OGlcNAcylation in response to phagocytotic stimuli.Knockout of the O-GlcNAc transferase or pharmacological inhibition of O-GlcNAcylation dramatically blocks phagocytosis,resulting in the disruption of retinal structure and function.Mechanistic studies reveal that the O-GlcNAc transferase interacts with Ezrin,a membrane-cytoskeleton linker protein,to catalyze its O-GlcNAcylation.Our data further show that Ezrin OGlcNAcylation promotes its localization to the cell cortex,thereby stimulating the membrane-cytoskeleton interaction needed for efficient phagocytosis.These findings identify a previously unrecognized role for protein O-GlcNAcylation in phagocytosis with important implications in both health and diseases.
基金supported by grants from the National Natural Science Foundation of China(31991193 and 32230025)the National Key R&D Program of China(2021YFA1101001).
文摘Carbohydrate metabolism disorders(CMDs),such as diabetes,galactosemia,and mannosidosis,cause ciliopathy-like multiorgan defects.However,the mechanistic link of cilia to CMD complications is still poorly understood.Herein,we describe significant cilium disassembly upon treatment of cells with pathologically relevant aldoses rather than the corresponding sugar alcohols.Moreover,environmental aldehydes are able to trigger cilium disassembly by the steric hindrance effect of their formyl groups.Mechanistic studies reveal that aldehydes stimulate extracellular calcium influx across the plasma membrane,which subsequently activates the calmodulin-Aurora A-histone deacetylase 6 pathway to deacetylate axonemal microtubules and triggers cilium disassembly.In vivo experiments further show that Hdac6 knockout mice are resistant to aldehyde-induced disassembly of tracheal cilia and sperm flagella.These findings reveal a previously unrecognized role for formyl group-mediated cilium disassembly in the complications of CMDs.
