Kazuki Okuyama, Motoi Yamashita, Artemis Koumoundourou, Christoph Wiegreffe, Michiko Ohno-Oishi, Samuel J. H. Murphy, Xin Zhao, Hideyuki Yoshida, Takashi Ebihara, Naoko Satoh-Takayama, Satoshi Kojo, Hiroshi Ohno, Tomohiro Morio, Yibo Wu, Jennifer Puck, Hai-Hui Xue, Stefan Britsch, Ichiro Taniuchi
{"title":"A mutant BCL11B-N440K protein interferes with BCL11A function during T lymphocyte and neuronal development","authors":"Kazuki Okuyama, Motoi Yamashita, Artemis Koumoundourou, Christoph Wiegreffe, Michiko Ohno-Oishi, Samuel J. H. Murphy, Xin Zhao, Hideyuki Yoshida, Takashi Ebihara, Naoko Satoh-Takayama, Satoshi Kojo, Hiroshi Ohno, Tomohiro Morio, Yibo Wu, Jennifer Puck, Hai-Hui Xue, Stefan Britsch, Ichiro Taniuchi","doi":"10.1038/s41590-024-01997-5","DOIUrl":null,"url":null,"abstract":"Genetic studies in mice have shown that the zinc finger transcription factor BCL11B has an essential role in regulating early T cell development and neurogenesis. A de novo heterozygous missense BCL11B variant, BCL11BN441K, was isolated from a patient with T cell deficiency and neurological disorders. Here, we show that mice harboring the corresponding Bcl11bN440K mutation show the emergence of natural killer (NK)/group 1 innate lymphoid cell (ILC1)-like NKp46+ cells in the thymus and reduction in TBR1+ neurons in the neocortex, which are observed with loss of Bcl11a but not Bcl11b. Thus, the mutant BCL11B-N440K protein interferes with BCL11A function upon heterodimerization. Mechanistically, the Bcl11bN440K mutation dampens the interaction of BCL11B with T cell factor 1 (TCF1) in thymocytes, resulting in weakened antagonism against TCF1 activity that supports the differentiation of NK/ILC1-like cells. Collectively, our results shed new light on the function of BCL11A in suppressing non-T lymphoid developmental potential and uncover the pathogenic mechanism by which BCL11B-N440K interferes with partner BCL11 family proteins. Taniuchi and colleagues describe the generation and phenotype of a mouse model carrying a defective Bcl11b allele encoding a mutant protein corresponding to BCL11B-N441K previously associated with human disease. They further characterize the molecular interactions between the mutant BCL11B protein and other transcription factors involved in early thymocyte development.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"25 12","pages":"2284-2296"},"PeriodicalIF":27.7000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s41590-024-01997-5","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Genetic studies in mice have shown that the zinc finger transcription factor BCL11B has an essential role in regulating early T cell development and neurogenesis. A de novo heterozygous missense BCL11B variant, BCL11BN441K, was isolated from a patient with T cell deficiency and neurological disorders. Here, we show that mice harboring the corresponding Bcl11bN440K mutation show the emergence of natural killer (NK)/group 1 innate lymphoid cell (ILC1)-like NKp46+ cells in the thymus and reduction in TBR1+ neurons in the neocortex, which are observed with loss of Bcl11a but not Bcl11b. Thus, the mutant BCL11B-N440K protein interferes with BCL11A function upon heterodimerization. Mechanistically, the Bcl11bN440K mutation dampens the interaction of BCL11B with T cell factor 1 (TCF1) in thymocytes, resulting in weakened antagonism against TCF1 activity that supports the differentiation of NK/ILC1-like cells. Collectively, our results shed new light on the function of BCL11A in suppressing non-T lymphoid developmental potential and uncover the pathogenic mechanism by which BCL11B-N440K interferes with partner BCL11 family proteins. Taniuchi and colleagues describe the generation and phenotype of a mouse model carrying a defective Bcl11b allele encoding a mutant protein corresponding to BCL11B-N441K previously associated with human disease. They further characterize the molecular interactions between the mutant BCL11B protein and other transcription factors involved in early thymocyte development.
期刊介绍:
Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.