Lysine 313 of T-box Is Crucial for Modulation of Protein Stability, DNA Binding, and Threonine Phosphorylation of T-bet
DC Field | Value | Language |
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dc.contributor.author | Jang, Eun Jung | - |
dc.contributor.author | Park, Hye Ryeon | - |
dc.contributor.author | Hong, Jeong-Ho | - |
dc.contributor.author | Hwang, Eun Sook | - |
dc.date.accessioned | 2021-09-06T00:44:40Z | - |
dc.date.available | 2021-09-06T00:44:40Z | - |
dc.date.created | 2021-06-18 | - |
dc.date.issued | 2013-06-01 | - |
dc.identifier.issn | 0022-1767 | - |
dc.identifier.uri | https://scholar.korea.ac.kr/handle/2021.sw.korea/102997 | - |
dc.description.abstract | AT-box containing protein expressed in T cells (T-bet) is a key transcription factor involved in the regulation of Th cell differentiation. Although T-bet deficient CD4(+) T cells fail to produce IFN-gamma and typically differentiate into Th2 cells in vitro, ectopic overexpression of T-bet elevates IFN-gamma and suppresses production of IL-2 and Th2 cytokines through different mechanisms Despite the importance of the T-bet protein level, the regulatory mechanisms that control T-bet protein stability are largely unknown. In this study, we found that T-bet underwent proteasomal degradation via ubiquitination at Lys-313. Despite its robust accumulation following lysine mutation, T-bet(K313R) failed to increase IFN-gamma production because of diminished DNA binding activity, as demonstrated in the crystal structure of T-bet DNA complex. Strikingly, T-bet(K313R) entirely lost the ability to suppress IL-2 production and Th2 cell development; this was due to loss of its interaction with NFAT1. We further identified that the T-bet(K313R) reduced the phosphorylation of Tbet at Thr-302, and that threonine phosphorylation was essential for T-bet interaction with NFAT1 and suppression of NFAT1 activity. Retroviral transduction of T-bet(T302A) into T-bet deficient cells restored IFN-gamma levels compared with those induced by wildtype T-bet, but this mutant failed to inhibit IL-2 and Th2 cytokine production. Collectively, these data show that Lys-313 in the T-box domain is essential for controlling T-bet protein stability via ubiquitin-dependent degradation, T-bet binding to the IFN-gamma promoter, and for the interaction with and suppression of NFAT1. Thus, multiple posttranslational modifications of T-bet are involved in fine-tuning cytokine production during Th cell development. | - |
dc.language | English | - |
dc.language.iso | en | - |
dc.publisher | AMER ASSOC IMMUNOLOGISTS | - |
dc.subject | TRANSCRIPTION FACTOR FOXP3 | - |
dc.subject | ROR-GAMMA-T | - |
dc.subject | GENE-EXPRESSION | - |
dc.subject | DEVELOPING HEART | - |
dc.subject | NUCLEAR FACTOR | - |
dc.subject | HELPER TYPE-1 | - |
dc.subject | CELLS | - |
dc.subject | DIFFERENTIATION | - |
dc.subject | LINEAGE | - |
dc.subject | SUBSET | - |
dc.title | Lysine 313 of T-box Is Crucial for Modulation of Protein Stability, DNA Binding, and Threonine Phosphorylation of T-bet | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Hong, Jeong-Ho | - |
dc.identifier.doi | 10.4049/jimmunol.1203403 | - |
dc.identifier.scopusid | 2-s2.0-84878073297 | - |
dc.identifier.wosid | 000319205900047 | - |
dc.identifier.bibliographicCitation | JOURNAL OF IMMUNOLOGY, v.190, no.11, pp.5764 - 5770 | - |
dc.relation.isPartOf | JOURNAL OF IMMUNOLOGY | - |
dc.citation.title | JOURNAL OF IMMUNOLOGY | - |
dc.citation.volume | 190 | - |
dc.citation.number | 11 | - |
dc.citation.startPage | 5764 | - |
dc.citation.endPage | 5770 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Immunology | - |
dc.relation.journalWebOfScienceCategory | Immunology | - |
dc.subject.keywordPlus | TRANSCRIPTION FACTOR FOXP3 | - |
dc.subject.keywordPlus | ROR-GAMMA-T | - |
dc.subject.keywordPlus | GENE-EXPRESSION | - |
dc.subject.keywordPlus | DEVELOPING HEART | - |
dc.subject.keywordPlus | NUCLEAR FACTOR | - |
dc.subject.keywordPlus | HELPER TYPE-1 | - |
dc.subject.keywordPlus | CELLS | - |
dc.subject.keywordPlus | DIFFERENTIATION | - |
dc.subject.keywordPlus | LINEAGE | - |
dc.subject.keywordPlus | SUBSET | - |
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