The p53 pathway is a highly complex signaling network including several key regulators.HAUSP is a critical component of the p53 pathway acting as a deubiquitinase for both p53 and its key repressor Mdm2.Here,we identi...The p53 pathway is a highly complex signaling network including several key regulators.HAUSP is a critical component of the p53 pathway acting as a deubiquitinase for both p53 and its key repressor Mdm2.Here,we identified a novel HAUSP-interacting protein,HLA-B-associated transcript 3(Bat3)and found it to be capable of inducing p53 stabilization and activation via a HAUSP-dependent mechanism,resulting in cell growth inhibition.Surprisingly,the deubiquitylating enzymatic activity of HAUSP was not required for this phenomenon.Co-immunoprecipitation showed that p53 coexisted in a complex with Bat3 and HAUSP in vivo,and HAUSP may serve as a binding mediator to enhance the interaction between p53 and Bat3.Further studies revealed that formation of this three-protein complex interfered with the binding of p53 to its proteasome receptor S5a and promoted the accumulation of p53 in nucleus.Notably,Mdm2 protein abundance is also regulated by Bat3 in the presence of HAUSP.Overexpression of Bat3 and HAUSP increases Mdm2 protein levels without influencing the p53–Mdm2 interaction and Mdm2-mediated p53 ubiquitination,indicating that Bat3–HAUSP-mediated protein stabilization is not specific to p53 and different mechanisms may be involved in Bat3-mediated regulation of p53–Mdm2 pathway.Together,our study unravels a novel mechanism by which p53 is stabilized and activated by HAUSP-mediated interaction with Bat3 and implies that Bat3 might function as a tumor suppressor through the stabilization of p53.展开更多
China Antimicrobial Resistance Surveillance Network for Pets(CARPet)was established in 2021 to monitor the resist-ance profiles of clinical bacterial pathogens from companion animals.From 2018 to 2021,we recovered and...China Antimicrobial Resistance Surveillance Network for Pets(CARPet)was established in 2021 to monitor the resist-ance profiles of clinical bacterial pathogens from companion animals.From 2018 to 2021,we recovered and tested 4,541 isolates from dogs and cats across 25 Chinese provinces,with Escherichia coli(18.5%)and Staphylococcus pseudintermedius(17.8%)being the most predominant bacterial species.The Enterobacterales were highly susceptible to tigecycline,meropenem,colistin,and amikacin(70.3%-100.0%),but showed moderate resistance to ampicillin,ceftriaxone,doxycycline,florfenicol,levofloxacin,enrofloxacin,and trimethoprim-sulfamethoxazole(29.3%-56.7%).About 66.3%of Acinetobacter spp.were resistant to florfenicol,with relatively low resistance to another 11 antibiot-ics(1.2%-23.3%).The Pseudomonas spp.showed high susceptibility to colistin(91.7%)and meropenem(88.3%).The coagulase-positive Staphylococcus spp.showed higher resistance rates to most antimicrobial agents than coagulase-negative Staphylococcus isolates.However,over 90.0%of Staphylococcus spp.were susceptible to linezolid,dapto-mycin and rifampin,and no vancomycin-resistant isolates were detected.E.faecium isolates demonstrated higher resistance rates to most antimicrobial agents than E.faecalis isolates.Streptococcus spp.isolates showed low resistance to most antimicrobial agents except for doxycycline(78.2%)and azithromycin(68.8%).Overall,the tested clinical isolates showed high rates of resistance to commonly used antimicrobial agents in companion animals.Therefore,it is crucial to strengthen the monitoring of bacterial resistance in pets.By timely and effectively collecting,analyzing,and reporting antimicrobial resistance dynamics in pets,the CARPet network will become a powerful platform to provide scientific guidance for both pet medical care and public health.展开更多
基金This work was supported by the National Natural Science Foundation of China(31500703,31371351,and 31671488)the Program for New Century Excellent Talents in University of China(NCET-09-0737).
文摘The p53 pathway is a highly complex signaling network including several key regulators.HAUSP is a critical component of the p53 pathway acting as a deubiquitinase for both p53 and its key repressor Mdm2.Here,we identified a novel HAUSP-interacting protein,HLA-B-associated transcript 3(Bat3)and found it to be capable of inducing p53 stabilization and activation via a HAUSP-dependent mechanism,resulting in cell growth inhibition.Surprisingly,the deubiquitylating enzymatic activity of HAUSP was not required for this phenomenon.Co-immunoprecipitation showed that p53 coexisted in a complex with Bat3 and HAUSP in vivo,and HAUSP may serve as a binding mediator to enhance the interaction between p53 and Bat3.Further studies revealed that formation of this three-protein complex interfered with the binding of p53 to its proteasome receptor S5a and promoted the accumulation of p53 in nucleus.Notably,Mdm2 protein abundance is also regulated by Bat3 in the presence of HAUSP.Overexpression of Bat3 and HAUSP increases Mdm2 protein levels without influencing the p53–Mdm2 interaction and Mdm2-mediated p53 ubiquitination,indicating that Bat3–HAUSP-mediated protein stabilization is not specific to p53 and different mechanisms may be involved in Bat3-mediated regulation of p53–Mdm2 pathway.Together,our study unravels a novel mechanism by which p53 is stabilized and activated by HAUSP-mediated interaction with Bat3 and implies that Bat3 might function as a tumor suppressor through the stabilization of p53.
基金financially supported by the National Key Research and Development Program of China(2022YFD1800400)Beijing Municipal Science and Technology Project(Z171100001517008).
文摘China Antimicrobial Resistance Surveillance Network for Pets(CARPet)was established in 2021 to monitor the resist-ance profiles of clinical bacterial pathogens from companion animals.From 2018 to 2021,we recovered and tested 4,541 isolates from dogs and cats across 25 Chinese provinces,with Escherichia coli(18.5%)and Staphylococcus pseudintermedius(17.8%)being the most predominant bacterial species.The Enterobacterales were highly susceptible to tigecycline,meropenem,colistin,and amikacin(70.3%-100.0%),but showed moderate resistance to ampicillin,ceftriaxone,doxycycline,florfenicol,levofloxacin,enrofloxacin,and trimethoprim-sulfamethoxazole(29.3%-56.7%).About 66.3%of Acinetobacter spp.were resistant to florfenicol,with relatively low resistance to another 11 antibiot-ics(1.2%-23.3%).The Pseudomonas spp.showed high susceptibility to colistin(91.7%)and meropenem(88.3%).The coagulase-positive Staphylococcus spp.showed higher resistance rates to most antimicrobial agents than coagulase-negative Staphylococcus isolates.However,over 90.0%of Staphylococcus spp.were susceptible to linezolid,dapto-mycin and rifampin,and no vancomycin-resistant isolates were detected.E.faecium isolates demonstrated higher resistance rates to most antimicrobial agents than E.faecalis isolates.Streptococcus spp.isolates showed low resistance to most antimicrobial agents except for doxycycline(78.2%)and azithromycin(68.8%).Overall,the tested clinical isolates showed high rates of resistance to commonly used antimicrobial agents in companion animals.Therefore,it is crucial to strengthen the monitoring of bacterial resistance in pets.By timely and effectively collecting,analyzing,and reporting antimicrobial resistance dynamics in pets,the CARPet network will become a powerful platform to provide scientific guidance for both pet medical care and public health.
