Heme regulates protein interactions and phosphorylation of BACH2 intrinsically disordered region in humoral response

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES iScience Pub Date : 2025-01-17 DOI:10.1016/j.isci.2024.111529

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

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Abstract

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.

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血红素调节体液反应中BACH2内在紊乱区的蛋白相互作用和磷酸化。

已知血红素与内在无序区（IDR）结合以调节蛋白质功能。血红素与转录因子BACH2的IDR结合促进浆细胞分化，但其分子基础尚不清楚。血红素增加了BACH2 IDR与TANK-binding kinase 1 （TBK1）的相互作用。TBK1通过磷酸化其IDR使BACH2失活，而BACH2则抑制TBK1基因的表达。TBK1磷酸化BACH2可抑制其与共抑制因子NCOR1的相互作用，促进浆细胞分化。血红素还诱导BACH2与泛素E3连接酶接头FBXO22结合，仅在血红素存在的情况下，体外多泛素化BACH2。TBK1介导的一些磷酸化位点的突变促进了BACH2-FBXO22的相互作用，而其他突变则消除了它们的相互作用，这表明TBK1既可以抑制也可以促进BACH2-FBXO22的相互作用。因此，血红素通过TBK1调控BACH2 IDR的磷酸化及其与NCOR1和FBXO22的相互作用，导致BACH2靶基因在体液免疫中的去抑制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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