TY - JOUR
T1 - Heme regulates protein interactions and phosphorylation of BACH2 intrinsically disordered region in humoral response
AU - Watanabe-Matsui, Miki
AU - Kadoya, Shun
AU - Segawa, Kei
AU - Shima, Hiroki
AU - Nakagawa, Tadashi
AU - Nagasawa, Yuko
AU - Hayashi, Shuichiro
AU - Matsumoto, Mitsuyo
AU - Ikeda, Mariko
AU - Muto, Akihiko
AU - Ochiai, Kyoko
AU - Nguyen, Long C.
AU - Doh-Ura, Katsumi
AU - Shirouzu, Mikako
AU - Nakayama, Keiko
AU - Murayama, Kazutaka
AU - Igarashi, Kazuhiko
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2025/1/17
Y1 - 2025/1/17
N2 - 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.
AB - 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.
KW - Biochemistry
KW - Structural biology
UR - http://www.scopus.com/inward/record.url?scp=85211756996&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85211756996&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2024.111529
DO - 10.1016/j.isci.2024.111529
M3 - Article
AN - SCOPUS:85211756996
SN - 2589-0042
VL - 28
JO - iScience
JF - iScience
IS - 1
M1 - 111529
ER -