IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development Journal Article
| Authors: | Goh, W.; Sudholz, H.; Foroutan, M.; Scheer, S.; Pfefferle, A.; Delconte, R. B.; Meng, X.; Shen, Z.; Hennessey, R.; Kong, I. Y.; Schuster, I. S.; Andoniou, C. E.; Davis, M. J.; Hediyeh-Zadeh, S.; Souza-Fonseca-Guimaraes, F.; Parish, I. A.; Beavis, P.; Thiele, D.; Chopin, M.; Degli-Esposti, M. A.; Cursons, J.; Kallies, A.; Rautela, J.; Nutt, S. L.; Huntington, N. D. |
| Article Title: | IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development |
| Abstract: | Ikaros transcription factors are essential for adaptive lymphocyte function, yet their role in innate lymphopoiesis is unknown. Using conditional genetic inactivation, we show that Ikzf1/Ikaros is essential for normal natural killer (NK) cell lymphopoiesis and IKZF1 directly represses Cish, a negative regulator of interleukin-15 receptor resulting in impaired interleukin-15 receptor signaling. Both Bcl2l11 and BIM levels, and intrinsic apoptosis were increased in Ikzf1-null NK cells, which in part accounts for NK lymphopenia as both were restored to normal levels when Ikzf1 and Bcl2l11 were co-deleted. Ikzf1-null NK cells presented extensive transcriptional alterations with reduced AP-1 transcriptional complex expression and increased expression of Ikzf2/Helios and Ikzf3/Aiolos. IKZF1 and IKZF3 directly bound AP-1 family members and deletion of both Ikzf1 and Ikzf3 in NK cells resulted in further reductions in Jun/Fos expression and complete loss of peripheral NK cells. Collectively, we show that Ikaros family members are important regulators of apoptosis, cytokine responsiveness and AP-1 transcriptional activity. © 2024, The Author(s), under exclusive licence to Springer Nature America, Inc. |
| Keywords: | controlled study; protein expression; genetics; nonhuman; mouse; metabolism; cell survival; cell cycle; gene expression; bone marrow; cell maturation; transcription initiation; cytokine; liver; natural killer cell; killer cells, natural; ex vivo study; lymphopoiesis; fluorescence activated cell sorting; mtor signaling; lymphocyte function; ikaros transcription factor; transcription factor ap 1; anaplastic large cell lymphoma; transcription factor ap-1; interleukin 15 receptor; article; rna sequencing; differential expression analysis; receptors, interleukin-15 |
| Journal Title: | Nature Immunology |
| Volume: | 25 |
| Issue: | 2 |
| ISSN: | 1529-2908 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-02-01 |
| Start Page: | 240 |
| End Page: | 255 |
| Language: | English |
| DOI: | 10.1038/s41590-023-01718-4 |
| PUBMED: | 38182668 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
