Immunosuppressive Yersinia Effector YopM Binds DEAD Box Helicase DDX3 to Control Ribosomal S6 Kinase in the Nucleus of Host Cells

YopM is an immunosuppressive virulence protein of pathogenic Yersinia species. After translocation into host cells it enters the nucleus but neither a nuclear activity nor the mechanisms underlying nucleocytoplasmic shuttling of YopM have been reported. Here we identify the DEAD-box helicase DDX3 as a novel interaction partner of YopM and describe a 2:1 YopM:DDX3 molecular complex in solution. Knockdown of DDX3 or inhibition of the exportin CRM1 increased the nuclear level of YopM and enhanced phosphorylation of nuclear Ribosomal S6 Kinase 1 (RSK1). Transcriptome analysis of Y. enterocolitica infected human macrophages revealed extensive suppression of immune/inflammatory pathways by YopM. Thus, YopM binds DDX3 to exit the nucleus via the CRM1 export pathway and the enabled nucleocytoplasmic shuttling of YopM adjusts phosphorylation of nuclear RSK1. These YopM activities result in a coordinated subversion of immune response pathways.