Ezrin,a membrane–cytoskeleton linker protein,plays an essential role in cell polarity establishment,cell migration,and division.Recent studies show that ezrin phosphorylation regulates breast cancer metastasis by pro...Ezrin,a membrane–cytoskeleton linker protein,plays an essential role in cell polarity establishment,cell migration,and division.Recent studies show that ezrin phosphorylation regulates breast cancer metastasis by promoting cancer cell survivor and promotes intrahepatic metastasis via cell migration.However,it was less characterized whether there are additional post-translational modifications and/or post-translational crosstalks on ezrin underlying context-dependent breast cancer cell migration and invasion.Here we show that ezrin is acetylated by p300/CBP-associated factor(PCAF)in breast cancer cells in response to CCL18 stimulation.Ezrin physically interacts with PCAF and is a cognate substrate of PCAF.The acetylation site of ezrin was mapped by mass spectrometric analyses,and dynamic acetylation of ezrin is essential for CCL18-induced breast cancer cell migration and invasion.Mechanistically,the acetylation reduced the lipid-binding activity of ezrin to ensure a robust and dynamic cycling between the plasma membrane and cytosol in response to CCL18 stimulation.Biochemical analyses show that ezrin acetylation prevents the phosphorylation of Thr567.Using atomic force microscopic measurements,our study revealed that acetylation of ezrin induced its unfolding into a dominant structure,which prevents ezrin phosphorylation at Thr567.Thus,these results present a previously undefined mechanism by which CCL18-elicited crosstalks between the acetylation and phosphorylation on ezrin control breast cancer cell migration and invasion.This suggests that targeting PCAF signaling could be a potential therapeutic strategy for combating hyperactive ezrin-driven cancer progression.展开更多
Dear Editor,The promptness and continuous expansion of the coronavirus disease 2019(COVID-19)pandemic,elicited by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and its variants,has presented an unpreceden...Dear Editor,The promptness and continuous expansion of the coronavirus disease 2019(COVID-19)pandemic,elicited by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and its variants,has presented an unprecedented impact on human health(WHO Coronavirus(COVID-19)Dashboard,2021).Although vaccination has attenuated the severe symptoms,there is no specific antiviral medication available for preventing the viral spread(Drayman et al.,2021).展开更多
Stable transmission of genetic information during cell division requires faithful mitotic spindle assembly and chromosome segregation.In eukaryotic cells,nuclear envelope breakdown(NEBD)is required for proper chromoso...Stable transmission of genetic information during cell division requires faithful mitotic spindle assembly and chromosome segregation.In eukaryotic cells,nuclear envelope breakdown(NEBD)is required for proper chromosome segregation.Although a list of mitotic kinases has been implicated in NEBD,how they coordinate their activity to dissolve the nuclear envelope and protein machinery such as nuclear pore complexes was unclear.Here,we identified a regulatory mechanism in which Nup62 is acetylated by TIP60 in human cell division.Nup62 is a novel substrate of TIP60,and the acetylation of Lys432 by TIP60 dissolves nucleoporin Nup62-Nup58-Nup54 complex during entry into mitosis.Importantly,this acetylation-elicited remodeling of nucleoporin complex promotes the distribution of Nup62 to the mitotic spindle,which is indispensable for orchestrating correct spindle orientation.Moreover,suppression of Nup62 perturbs accurate chromosome segregation during mitosis.These results establish a previously uncharacterized regulatory mechanism in which TIP60-elicited nucleoporin dynamics promotes chromosome segregation in mitosis.展开更多
基金This work was supported in part by grants from the National Natural Science Foundation of China(81630080,31430054,91854203,31301105,31320103904,31621002,31671405,91853115,21922706,81572283,31271518,31471275,and 31870759)National Key Research and Development Program of China(2017YFA0503600 and 2016YFA0100500)+2 种基金Ministry of Education(IRT_17R102 and 20113402130010)the Strategic Priority Research Program of Chinese Academy of Sciences(XDB19000000)Central University Grants WK2340000066.
文摘Ezrin,a membrane–cytoskeleton linker protein,plays an essential role in cell polarity establishment,cell migration,and division.Recent studies show that ezrin phosphorylation regulates breast cancer metastasis by promoting cancer cell survivor and promotes intrahepatic metastasis via cell migration.However,it was less characterized whether there are additional post-translational modifications and/or post-translational crosstalks on ezrin underlying context-dependent breast cancer cell migration and invasion.Here we show that ezrin is acetylated by p300/CBP-associated factor(PCAF)in breast cancer cells in response to CCL18 stimulation.Ezrin physically interacts with PCAF and is a cognate substrate of PCAF.The acetylation site of ezrin was mapped by mass spectrometric analyses,and dynamic acetylation of ezrin is essential for CCL18-induced breast cancer cell migration and invasion.Mechanistically,the acetylation reduced the lipid-binding activity of ezrin to ensure a robust and dynamic cycling between the plasma membrane and cytosol in response to CCL18 stimulation.Biochemical analyses show that ezrin acetylation prevents the phosphorylation of Thr567.Using atomic force microscopic measurements,our study revealed that acetylation of ezrin induced its unfolding into a dominant structure,which prevents ezrin phosphorylation at Thr567.Thus,these results present a previously undefined mechanism by which CCL18-elicited crosstalks between the acetylation and phosphorylation on ezrin control breast cancer cell migration and invasion.This suggests that targeting PCAF signaling could be a potential therapeutic strategy for combating hyperactive ezrin-driven cancer progression.
基金supported by NIH grants(DK56292,DK115812,U54MD007602-33S3,S21MD000101,and CA164133).
文摘Dear Editor,The promptness and continuous expansion of the coronavirus disease 2019(COVID-19)pandemic,elicited by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and its variants,has presented an unprecedented impact on human health(WHO Coronavirus(COVID-19)Dashboard,2021).Although vaccination has attenuated the severe symptoms,there is no specific antiviral medication available for preventing the viral spread(Drayman et al.,2021).
基金supported by grants from the National Key Re-search and Development Program of China(2017YFA0503600 and 2016YFA0100500)the National Natural Science Founda-tion of China(31621002,32090040,91854203,21922706,91853115,92153302,22177106,92053104,31970655,and 32100612)+2 种基金the Ministry of Education(IRT_17R102),Anhui Provincial Natural Science Foundation(2108085J15)the Strate-gic Priority Research Program of the Chinese Academy of Sci-ences(XDB19040000)the Fundamental Research Funds for the Central Universities(WK2070000066 and WK2070000194).
文摘Stable transmission of genetic information during cell division requires faithful mitotic spindle assembly and chromosome segregation.In eukaryotic cells,nuclear envelope breakdown(NEBD)is required for proper chromosome segregation.Although a list of mitotic kinases has been implicated in NEBD,how they coordinate their activity to dissolve the nuclear envelope and protein machinery such as nuclear pore complexes was unclear.Here,we identified a regulatory mechanism in which Nup62 is acetylated by TIP60 in human cell division.Nup62 is a novel substrate of TIP60,and the acetylation of Lys432 by TIP60 dissolves nucleoporin Nup62-Nup58-Nup54 complex during entry into mitosis.Importantly,this acetylation-elicited remodeling of nucleoporin complex promotes the distribution of Nup62 to the mitotic spindle,which is indispensable for orchestrating correct spindle orientation.Moreover,suppression of Nup62 perturbs accurate chromosome segregation during mitosis.These results establish a previously uncharacterized regulatory mechanism in which TIP60-elicited nucleoporin dynamics promotes chromosome segregation in mitosis.
