Activation-induced cytidine deaminase(AID)initiates class-switch recombination and somatic hypermutation(SHM)in antibody genes.Protein expression and activity are tightly controlled by various mechanisms.However,it re...Activation-induced cytidine deaminase(AID)initiates class-switch recombination and somatic hypermutation(SHM)in antibody genes.Protein expression and activity are tightly controlled by various mechanisms.However,it remains unknown whether a signal from the extracellular environment directly affects the AID activity in the nucleus where it works.Here,we demonstrated that a deubiquitinase USP10,which specifically stabilizes nuclear AID protein,can translocate into the nucleus after AKT-mediated phosphorylation at its T674 within the NLS domain.Interestingly,the signals from BCR and TLR1/2 synergistically promoted this phosphorylation.The deficiency of USP10 in B cells significantly decreased AID protein levels,subsequently reducing neutralizing antibody production after immunization with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)or human immunodeficiency virus type 1(HIV-1)nanoparticle vaccines.Collectively,we demonstrated that USP10 functions as an integrator for both BCR and TLR signals and directly regulates nuclear AID activity.Its manipulation could be used for the development of vaccines and adjuvants.展开更多
基金This work was supported by the National Special Research Program of China for Important Infectious Diseases(2017ZX10202102 and 2018ZX10302103)the Special 2019-nCoV Project of the National Key Research and Development Program of China(2020YFC0841400)the Special 2019-nCoV Program of the Natural Science Foundation of China(NSFC)(82041002),the Emergency Key Program of Guangzhou Laboratory(EKPG21-24),the Important Key Program of NSFC(81730060),and the Joint-Innovation Program in Healthcare for Special Scientific Research Projects of Guangzhou(201803040002)to Hui Zhang,the Postdoctoral Science Foundation of China(2019M663249,2020M683032)to Yuewen Luo and Jun Liu,the Guangdong Basic and Applied Basic Research Foundation(2020A1515110807)to Yuewen Luo and the Fundamental Research Funds for the Central Universities(20ykpy138)to Yuewen Luo.
文摘Activation-induced cytidine deaminase(AID)initiates class-switch recombination and somatic hypermutation(SHM)in antibody genes.Protein expression and activity are tightly controlled by various mechanisms.However,it remains unknown whether a signal from the extracellular environment directly affects the AID activity in the nucleus where it works.Here,we demonstrated that a deubiquitinase USP10,which specifically stabilizes nuclear AID protein,can translocate into the nucleus after AKT-mediated phosphorylation at its T674 within the NLS domain.Interestingly,the signals from BCR and TLR1/2 synergistically promoted this phosphorylation.The deficiency of USP10 in B cells significantly decreased AID protein levels,subsequently reducing neutralizing antibody production after immunization with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)or human immunodeficiency virus type 1(HIV-1)nanoparticle vaccines.Collectively,we demonstrated that USP10 functions as an integrator for both BCR and TLR signals and directly regulates nuclear AID activity.Its manipulation could be used for the development of vaccines and adjuvants.
