USP10 regulates B cell response to SARS-CoV-2 or HIV-1 nanoparticle vaccines through deubiquitinating AID

Yuewen Luo,Meijun Si,Yang Liu,Xiantao Zhang,Ting Pan,Yiwen Zhang,Qin Liu,Xuemei Wang,Bolin Wu,Xu Zhang,Shijian Wu,Hui Zhang,Rong Li,Jun Liu,Junsong Zhang,Deyin Guo,Ran Chen,Xin He

doi:10.1038/s41392-021-00858-z

Abstract

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.

Highlights

Facing the challenge of antigens including those derived from numerous pathogens, individuals need to produce billions of antibodies using limited genes
Most Activation-induced cytidine deaminase (AID) is retained in the cytoplasm by interacting with eEF1A and HSP90 to hinder the passive diffusion of AID into the nucleus.[33,34,36,60,61]
Once AID is imported by GANP and/or importin, it is quickly exported back to the cytoplasm by CRM1 or degraded by the proteasome pathway in the nucleus.[28,37,40,62,63]

Summary

Introduction

Facing the challenge of antigens including those derived from numerous pathogens, individuals need to produce billions of antibodies using limited genes. SHM induces numerous point mutations in the variable region of the Ig genes, which provides the driving force for the antibody selection for various antigens, leading to the generation of higher-affinity antibodies.[1] In addition, individuals need different types of antibodies to perform different functions, such as IgA antibody for mucosal immunity or IgE antibody for antiparasitic immunity. To this end, class-switch recombination (CSR) is required for multi-class antibody development. To increase the humoral immune response to the vaccine, it is reasonable to increase the proper expression or activity of AID during antigen immunization

Methods

Results

Conclusion