title: SRSF1-3 contributes to diversification of the immunoglobulin variable region gene by promoting accumulation of AID in the nucleus.
abstract: Activation-induced cytidine deaminase (AID) is essential for diversification of the Ig variable region (IgV). AID is excluded from the nucleus, where it normally functions. However, the molecular mechanisms responsible for regulating AID localization remain to be elucidated. The SR-protein splicing factor SRSF1 is a nucleocytoplasmic shuttling protein, a splicing isoform of which called SRSF1-3, has previously been shown to contribute to IgV diversification in chicken DT40 cells. In this study, we examined whether SRSF1-3 functions in IgV diversification by promoting nuclear localization of AID. AID expressed alone was localized predominantly in the cytoplasm. In contrast, co-expression of AID with SRSF1-3 led to the nuclear accumulation of both AID and SRSF1-3 and the formation of a protein complex that contained them both, although SRSF1-3 was dispensable for nuclear import of AID. Expression of either SRSF1-3 or a C-terminally-truncated AID mutant increased IgV diversification in DT40 cells. However, overexpression of exogenous SRSF1-3 was unable to further enhance IgV diversification in DT40 cells expressing the truncated AID mutant, although SRSF1-3 was able to form a protein complex with the AID mutant. These results suggest that SRSF1-3 promotes nuclear localization of AID probably by forming a nuclear protein complex, which might stabilize nuclear AID and induce IgV diversification in an AID C-terminus-dependent manner.
authors.affiliation: Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kawaguchi
authors.affiliation: Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nariki
authors.affiliation: Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kawamoto
authors.affiliation: Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kanehiro
authors.affiliation: Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyazaki
authors.affiliation: Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Magari
authors.affiliation: Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tokumitsu
authors.affiliation: Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan. Electronic address: nkanayam@okayama-u.ac.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kanayama
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D030161:Avian Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002645:Chickens / Q000235:genetics* / Q000378:metabolism; D003564:Cytidine Deaminase / Q000378:metabolism*; D005785:Gene Conversion; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors / Q000378:metabolism*; D027041:Somatic Hypermutation, Immunoglobulin; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D030161:Avian Proteins; D007135:Immunoglobulin Variable Region; D000068103:Serine-Arginine Splicing Factors; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
keywords: AID; DT40; Gene conversion; Ig; SRSF1; Somatic hypermutation