Heme regulates protein interactions and phosphorylation of BACH2 intrinsically disordered region in humoral response
Miki Watanabe-Matsui,
Shun Kadoya,
Kei Segawa,
Hiroki Shima,
Tadashi Nakagawa,
Yuko Nagasawa,
Shuichiro Hayashi,
Mitsuyo Matsumoto,
Mariko Ikeda,
Akihiko Muto,
Kyoko Ochiai,
Long C. Nguyen,
Katsumi Doh-Ura,
Mikako Shirouzu,
Keiko Nakayama,
Kazutaka Murayama,
Kazuhiko Igarashi
Affiliations
Miki Watanabe-Matsui
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; The Japan Society for the Promotion of Science (JSPS), Tokyo, Japan
Shun Kadoya
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
Kei Segawa
Pharmaceutical Discovery Research Laboratories, Teijin Pharma Limited, Tokyo, Japan
Hiroki Shima
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
Tadashi Nakagawa
Division of Cell Proliferation, ART, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Clinical Pharmacology, Sanyo-Onoda City University, Sanyo-Onoda, Japan
Yuko Nagasawa
Division of Cell Proliferation, ART, Tohoku University Graduate School of Medicine, Sendai, Japan
Shuichiro Hayashi
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
Mitsuyo Matsumoto
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
Mariko Ikeda
Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Japan
Akihiko Muto
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
Kyoko Ochiai
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
Long C. Nguyen
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
Katsumi Doh-Ura
Department of Neurochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
Mikako Shirouzu
Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Japan
Keiko Nakayama
Division of Cell Proliferation, ART, Tohoku University Graduate School of Medicine, Sendai, Japan
Kazutaka Murayama
Division of Biomedical Measurements and Diagnostics, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan
Kazuhiko Igarashi
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Corresponding author
Summary: Heme is known to bind to the intrinsically disordered region (IDR) to regulate protein function. The binding of heme to the IDR of transcription factor BACH2 promotes plasma cell differentiation, but the molecular basis is unknown. Heme was found to increase BACH2 IDR interaction with TANK-binding kinase 1 (TBK1). TBK1 inactivated BACH2 by phosphorylation of its IDR, whereas BACH2 repressed TBK1 gene expression. BACH2 phosphorylation by TBK1 inhibited its interaction with the co-repressor NCOR1 and promoted plasma cell differentiation. Heme also induced BACH2 binding to ubiquitin E3 ligase adaptor FBXO22, which polyubiquitinated BACH2 only in the presence of heme in vitro. Mutations of some of the TBK1-mediated phosphorylation sites promoted BACH2-FBXO22 interaction, while additional mutations abrogated their interaction, suggesting that TBK1 can both inhibit and promote BACH2-FBXO22 interaction. Therefore, heme regulates phosphorylation of BACH2 IDR by TBK1 and its interaction with NCOR1 and FBXO22, leading to de-repression of BACH2 target genes in humoral immunity.
