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Perturbation of Ddx3x on the mouse X-chromosome in all hematopoietic cells resulted in a loss of natural killer (NK) cells, yet whether DDX3X is important only in progenitors or within NK cells remained unexplored. Herein, we deleted Ddx3x from committed NK cells by crossing Ddx3x-floxed mice to Ncr1-iCre mice. The resulting Cre+ offspring exhibited a profound deficiency of NK cells in the spleen and bone marrow. Ncr1-iCre\u2013mediated deletion of Ddx3x also blocked in vitro generation of NK cells. CRISPR-mediated deletion of Ddx3x or pharmacological inhibition of DDX3 helicase activity in mature mouse NK cells resulted in rapid loss of cell viability, consistent with a role for DDX3X in NK cell survival. Indeed, perturbation of DDX3X in NK cells caused a substantial decrease in protein expression levels of the prosurvival mediator MCL1 but did not affect expression of the related prosurvival proteins BCL-2 or BCL-xL. Genetic deletion of the pro-apoptotic targets of MCL1, Bak and Bax, rescued the survival of NK cells following inhibition of DDX3. Mechanistically, expression levels of Mcl1 mRNA and proteasomal degradation of MCL1 protein were independent of DDX3. Instead, DDX3 bolstered MCL1 expression by supporting de novo translation of MCL1 protein. Collectively, these findings highlight a crucial role for the RNA helicase DDX3X in maintaining the NK cell compartment by supporting efficient translation of MCL1.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf281","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T16:05:41Z","timestamp":1760630741000},"page":"3218-3227","source":"Crossref","is-referenced-by-count":1,"title":["RNA helicase DDX3X promotes NK cell survival by supporting MCL1 expression"],"prefix":"10.1093","volume":"214","author":[{"given":"Eshana","family":"Mukhopadhyay","sequence":"first","affiliation":[{"name":"Development, Stem Cells, and Regenerative Medicine Graduate Program, University of Cincinnati College of Medicine , Cincinnati, OH,","place":["United States"]},{"name":"Center for Autoimmune Genomics and Etiology, Division of Human Genetics, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH,","place":["United 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States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9896-9714","authenticated-orcid":false,"given":"Jasmine A","family":"Tuazon","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Division of Human Genetics, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David E","family":"Ohayon","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Division of Human Genetics, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayad","family":"Ali","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Division of Human Genetics, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH,","place":["United 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States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A","family":"Hildeman","sequence":"additional","affiliation":[{"name":"Immunology Graduate Program, University of Cincinnati College of Medicine , Cincinnati, OH,","place":["United States"]},{"name":"Medical Scientist Training Program, University of Cincinnati College of Medicine , Cincinnati, OH,","place":["United States"]},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine , Cincinnati, OH,","place":["United States"]},{"name":"Division of Immunobiology, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9658-2874","authenticated-orcid":false,"given":"Stephen N","family":"Waggoner","sequence":"additional","affiliation":[{"name":"Development, Stem Cells, and Regenerative Medicine Graduate Program, University of Cincinnati College of Medicine , Cincinnati, OH,","place":["United States"]},{"name":"Center for Autoimmune Genomics and Etiology, Division of Human Genetics, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH,","place":["United States"]},{"name":"Immunology Graduate Program, University of Cincinnati College of Medicine , Cincinnati, OH,","place":["United States"]},{"name":"Medical Scientist Training Program, University of Cincinnati College of Medicine , Cincinnati, OH,","place":["United States"]},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine , Cincinnati, OH,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"2025122315370313100_vkaf281-B1","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/s41580-023-00628-5","article-title":"Cellular functions of eukaryotic RNA helicases and their links to human 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