title: Activation-induced cytidine deaminase (AID) is localized to subnuclear domains enriched in splicing factors.
abstract: Activation-induced cytidine deaminase (AID) is the mutator enzyme in adaptive immunity. AID initiates the antibody diversification processes in activated B cells by deaminating cytosine to uracil in immunoglobulin genes. To some extent other genes are also targeted, which may lead to genome instability and B cell malignancy. Thus, it is crucial to understand its targeting and regulation mechanisms. AID is regulated at several levels including subcellular compartmentalization. However, the complex nuclear distribution and trafficking of AID has not been studied in detail previously. In this work, we examined the subnuclear localization of AID and its interaction partner CTNNBL1 and found that they associate with spliceosome-associated structures including Cajal bodies and nuclear speckles. Moreover, protein kinase A (PKA), which activates AID by phosphorylation at Ser38, is present together with AID in nuclear speckles. Importantly, we demonstrate that AID physically associates with the major spliceosome subunits (small nuclear ribonucleoproteins, snRNPs), as well as other essential splicing components, in addition to the transcription machinery. Based on our findings and the literature, we suggest a transcription-coupled splicing-associated model for AID targeting and activation.
authors.affiliation: Central Norway Health Authorities and Department of Cancer Research and Molecular Medicine, Faculty of Medicine, NTNU, N-7491, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: yihooyi@gmail.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Central Norway Health Authorities and Department of Cancer Research and Molecular Medicine, Faculty of Medicine, NTNU, N-7491, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: ida.ericsson@ntnu.no.
authors.forename: Ida
authors.initials: I
authors.lastname: Ericsson
authors.affiliation: Central Norway Health Authorities and Department of Cancer Research and Molecular Medicine, Faculty of Medicine, NTNU, N-7491, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: berit.doseth@ntnu.no.
authors.forename: Berit
authors.initials: B
authors.lastname: Doseth
authors.affiliation: Central Norway Health Authorities and Department of Cancer Research and Molecular Medicine, Faculty of Medicine, NTNU, N-7491, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: nina.beate.liabakk@ntnu.no.
authors.forename: Nina B
authors.initials: NB
authors.lastname: Liabakk
authors.affiliation: Central Norway Health Authorities and Department of Cancer Research and Molecular Medicine, Faculty of Medicine, NTNU, N-7491, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: hans.krokan@ntnu.no.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Krokan
authors.affiliation: Central Norway Health Authorities and Department of Cancer Research and Molecular Medicine, Faculty of Medicine, NTNU, N-7491, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: bodil.kavli@ntnu.no.
authors.forename: Bodil
authors.initials: B
authors.lastname: Kavli
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002478:Cells, Cultured; D020541:Coiled Bodies / Q000378:metabolism; D003564:Cytidine Deaminase / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D012326:RNA Splicing; D017411:Ribonucleoproteins, Small Nuclear / Q000378:metabolism; D017381:Spliceosomes / Q000378:metabolism*; D014018:Tissue Distribution; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D051017:Apoptosis Regulatory Proteins; C479429:CTNNBL1 protein, human; D009687:Nuclear Proteins; D017411:Ribonucleoproteins, Small Nuclear; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
keywords: Activation-induced cytidine deaminase; CTNNBL1; Cajal bodies; Nuclear speckles; Subnuclear trafficking; Transcription-coupled splicing