DDX3X promotes NK cell survival by facilitating translation of MCL1 2501

Abstract Description DEAD-box RNA helicases, such as DDX3X on the X-chromosome, play critical roles in regulating nuclear export, translation, splicing, and metabolism of RNA. Based on recent evidence of X-chromosome mediated regulation of sexual dimorphism in natural killer (NK) cell biology, we sought to determine the role of DDX3X in NK cells. Targeted disruption of DDX3X expression in mouse NK cells using tamoxifen-inducible Cre excision of floxed Ddx3x alleles, CRISPR, or a pharmacologic DDX3 inhibitor resulted in a marked loss of NK cells. This was associated with reduced protein levels of the pro-survival factor MCL1 but normal expression of BCL2 and BCL-xL. Similar results were obtained following pharmacological inhibition of DDX3 activity in human NK cells. Mcl1 expression at the mRNA level is not affected by loss of DDX3X. Experiments with cycloheximide and proteosome inhibitor reveal that DDX3X affects protein levels of MCL1 by promoting translation rather than by preventing proteasomal degradation of this short-lived survival protein. Indeed, immunoprecipitation of DDX3X in mouse NK cells marked enriched Mcl1 transcripts. Collectively, these findings highlight the crucial role of DDX3X in maintaining the NK cell compartment by supporting efficient translation of MCL1. Funding Sources American Heart Association, Cincinnati Children Research Foundation Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)