Heme regulates protein interactions and phosphorylation of BACH2 intrinsically disordered region in humoral response
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-...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224027561 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850109486436450304 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Miki Watanabe-Matsui |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-98d104f654714a66b85ac8f7fb33ee3c |
| institution | OA Journals |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-98d104f654714a66b85ac8f7fb33ee3c2025-08-20T02:38:03ZengElsevieriScience2589-00422025-01-0128111152910.1016/j.isci.2024.111529Heme regulates protein interactions and phosphorylation of BACH2 intrinsically disordered region in humoral responseMiki Watanabe-Matsui0Shun Kadoya1Kei Segawa2Hiroki Shima3Tadashi Nakagawa4Yuko Nagasawa5Shuichiro Hayashi6Mitsuyo Matsumoto7Mariko Ikeda8Akihiko Muto9Kyoko Ochiai10Long C. Nguyen11Katsumi Doh-Ura12Mikako Shirouzu13Keiko Nakayama14Kazutaka Murayama15Kazuhiko Igarashi16Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; The Japan Society for the Promotion of Science (JSPS), Tokyo, JapanDepartment of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, JapanPharmaceutical Discovery Research Laboratories, Teijin Pharma Limited, Tokyo, JapanDepartment of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, JapanDivision of Cell Proliferation, ART, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Clinical Pharmacology, Sanyo-Onoda City University, Sanyo-Onoda, JapanDivision of Cell Proliferation, ART, Tohoku University Graduate School of Medicine, Sendai, JapanDepartment of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, JapanDepartment of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, JapanLaboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, JapanDepartment of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, JapanDepartment of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, JapanDepartment of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, JapanDepartment of Neurochemistry, Tohoku University Graduate School of Medicine, Sendai, JapanLaboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, JapanDivision of Cell Proliferation, ART, Tohoku University Graduate School of Medicine, Sendai, JapanDivision of Biomedical Measurements and Diagnostics, Tohoku University Graduate School of Biomedical Engineering, Sendai, JapanDepartment of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004224027561BiochemistryStructural biology |
| spellingShingle | 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 Heme regulates protein interactions and phosphorylation of BACH2 intrinsically disordered region in humoral response iScience Biochemistry Structural biology |
| title | Heme regulates protein interactions and phosphorylation of BACH2 intrinsically disordered region in humoral response |
| title_full | Heme regulates protein interactions and phosphorylation of BACH2 intrinsically disordered region in humoral response |
| title_fullStr | Heme regulates protein interactions and phosphorylation of BACH2 intrinsically disordered region in humoral response |
| title_full_unstemmed | Heme regulates protein interactions and phosphorylation of BACH2 intrinsically disordered region in humoral response |
| title_short | Heme regulates protein interactions and phosphorylation of BACH2 intrinsically disordered region in humoral response |
| title_sort | heme regulates protein interactions and phosphorylation of bach2 intrinsically disordered region in humoral response |
| topic | Biochemistry Structural biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224027561 |
| work_keys_str_mv | AT mikiwatanabematsui hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT shunkadoya hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT keisegawa hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT hirokishima hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT tadashinakagawa hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT yukonagasawa hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT shuichirohayashi hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT mitsuyomatsumoto hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT marikoikeda hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT akihikomuto hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT kyokoochiai hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT longcnguyen hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT katsumidohura hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT mikakoshirouzu hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT keikonakayama hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT kazutakamurayama hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse AT kazuhikoigarashi hemeregulatesproteininteractionsandphosphorylationofbach2intrinsicallydisorderedregioninhumoralresponse |