USP10 Regulates B Cell Response to SARS-CoV-2 or HIV-1 Nanoparticle Vaccines Through Deubiquitinating AID

Overview

Journal Signal Transduct Target Ther

Specialties Cell Biology
Pharmacology

Date 2022 Jan 5

PMID 34983926

Citations 5

Authors

Yuewen Luo

Xiantao Zhang

Ran Chen

Rong Li

Yang Liu

Junsong Zhang

Qin Liu

Meijun Si

Jun Liu

Bolin Wu

Xuemei Wang

Shijian Wu

Yiwen Zhang

Xu Zhang

Deyin Guo

Xin He

Ting Pan

Hui Zhang

Affiliations

Soon will be listed here.

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.

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References

Di Noia J, Neuberger M . Molecular mechanisms of antibody somatic hypermutation. Annu Rev Biochem. 2007; 76:1-22. DOI: 10.1146/annurev.biochem.76.061705.090740. View

Stavnezer J, Guikema J, Schrader C . Mechanism and regulation of class switch recombination. Annu Rev Immunol. 2008; 26:261-92. PMC: 2707252. DOI: 10.1146/annurev.immunol.26.021607.090248. View

Revy P, Muto T, Levy Y, Geissmann F, Plebani A, Sanal O . Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell. 2000; 102(5):565-75. DOI: 10.1016/s0092-8674(00)00079-9. View

Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T . Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell. 2000; 102(5):553-63. DOI: 10.1016/s0092-8674(00)00078-7. View

Feng Y, Seija N, Di Noia J, Martin A . AID in Antibody Diversification: There and Back Again. Trends Immunol. 2020; 41(7):586-600. PMC: 7183997. DOI: 10.1016/j.it.2020.04.009. View

Zhang X, Zhang Y, Ba Z, Kyritsis N, Casellas R, Alt F . Fundamental roles of chromatin loop extrusion in antibody class switching. Nature. 2019; 575(7782):385-389. PMC: 6856444. DOI: 10.1038/s41586-019-1723-0. View

Roco J, Mesin L, Binder S, Nefzger C, Gonzalez-Figueroa P, Canete P . Class-Switch Recombination Occurs Infrequently in Germinal Centers. Immunity. 2019; 51(2):337-350.e7. PMC: 6914312. DOI: 10.1016/j.immuni.2019.07.001. View

Khurana S, Frasca D, Blomberg B, Golding H . AID activity in B cells strongly correlates with polyclonal antibody affinity maturation in-vivo following pandemic 2009-H1N1 vaccination in humans. PLoS Pathog. 2012; 8(9):e1002920. PMC: 3441753. DOI: 10.1371/journal.ppat.1002920. View

Robbiani D, Nussenzweig M . Chromosome translocation, B cell lymphoma, and activation-induced cytidine deaminase. Annu Rev Pathol. 2012; 8:79-103. DOI: 10.1146/annurev-pathol-020712-164004. View

10.

Ramiro A, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, Muramatsu M . AID is required for c-myc/IgH chromosome translocations in vivo. Cell. 2004; 118(4):431-8. DOI: 10.1016/j.cell.2004.08.006. View

11.

Huy Tran T, Nakata M, Suzuki K, Begum N, Shinkura R, Fagarasan S . B cell-specific and stimulation-responsive enhancers derepress Aicda by overcoming the effects of silencers. Nat Immunol. 2009; 11(2):148-54. DOI: 10.1038/ni.1829. View

12.

Park S, Zan H, Pal Z, Zhang J, Al-Qahtani A, Pone E . HoxC4 binds to the promoter of the cytidine deaminase AID gene to induce AID expression, class-switch DNA recombination and somatic hypermutation. Nat Immunol. 2009; 10(5):540-50. PMC: 2753990. DOI: 10.1038/ni.1725. View

13.

Bossen C, Schneider P . BAFF, APRIL and their receptors: structure, function and signaling. Semin Immunol. 2006; 18(5):263-75. DOI: 10.1016/j.smim.2006.04.006. View

14.

He B, Santamaria R, Xu W, Cols M, Chen K, Puga I . The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88. Nat Immunol. 2010; 11(9):836-45. PMC: 3047500. DOI: 10.1038/ni.1914. View

15.

Xu Z, Zan H, Pone E, Mai T, Casali P . Immunoglobulin class-switch DNA recombination: induction, targeting and beyond. Nat Rev Immunol. 2012; 12(7):517-31. PMC: 3545482. DOI: 10.1038/nri3216. View

16.

Pone E, Zhang J, Mai T, White C, Li G, Sakakura J . BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-κB pathway. Nat Commun. 2012; 3:767. PMC: 3337981. DOI: 10.1038/ncomms1769. View

17.

Basso K, Schneider C, Shen Q, Holmes A, Setty M, Leslie C . BCL6 positively regulates AID and germinal center gene expression via repression of miR-155. J Exp Med. 2012; 209(13):2455-65. PMC: 3526356. DOI: 10.1084/jem.20121387. View

18.

Teng G, Hakimpour P, Landgraf P, Rice A, Tuschl T, Casellas R . MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity. 2008; 28(5):621-9. PMC: 2430982. DOI: 10.1016/j.immuni.2008.03.015. View

19.

de Yebenes V, Belver L, Pisano D, Gonzalez S, Villasante A, Croce C . miR-181b negatively regulates activation-induced cytidine deaminase in B cells. J Exp Med. 2008; 205(10):2199-206. PMC: 2556787. DOI: 10.1084/jem.20080579. View

20.

Borchert G, Holton N, Larson E . Repression of human activation induced cytidine deaminase by miR-93 and miR-155. BMC Cancer. 2011; 11:347. PMC: 3163633. DOI: 10.1186/1471-2407-11-347. View