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

PLoS Pathogens

Malik Alawi¹  Friedrich Koch-Nolte²  Alexey G. Kikhney³  Adam Grundhoff³  Dmitri I. Svergun⁴  Martin Aepfelbacher⁴  Markus Perbandt⁵  Friedrich Buck⁶  Klaus Ruckdeschel⁷  Andreas Rumm⁷  Christian Betzel⁷  Marie Schnapp⁷  Laura Berneking⁷  Claudia Trasak⁷  Moritz Hentschke⁸ 

[1] Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;European Molecular Biology Laboratory (EMBL), Hamburg Outstation, Hamburg, Germany;Heinrich-Pette-Institute (HPI), Leibniz Institute for Experimental Virology, Research Group Virus Genomics, Hamburg, Germany;Institute of Biochemistry and Molecular Biology, University of Hamburg, Laboratory of Structural Biology of Infection and Inflammation, Hamburg, Germany;Institute of Clinical Chemistry, University Medical Center, Hamburg, Germany;Institute of Immunology, University Medical Center, Hamburg, Germany;Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany;The Hamburg Centre for Ultrafast Imaging, Hamburg, Germany

关键词: Macrophages;    Phosphorylation;    Small interfering RNAs;    Yersinia enterocolitica;    Crystal structure;    Yersinia;    Yersinia pestis;    Gene expression;   

DOI  :  10.1371/journal.ppat.1005660

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Yersinia outer protein M (YopM) is a crucial immunosuppressive effector of the plaque agent Yersinia pestis and other pathogenic Yersinia species. YopM enters the nucleus of host cells but neither the mechanisms governing its nucleocytoplasmic shuttling nor its intranuclear activities are known. Here we identify the DEAD-box helicase 3 (DDX3) as a novel interaction partner of Y. enterocolitica YopM and present the three-dimensional structure of a YopM:DDX3 complex. Knockdown of DDX3 or inhibition of the exportin chromosomal maintenance 1 (CRM1) increased the nuclear level of YopM suggesting that YopM exploits DDX3 to exit the nucleus via the CRM1 export pathway. Increased nuclear YopM levels caused enhanced phosphorylation of Ribosomal S6 Kinase 1 (RSK1) in the nucleus. In Y. enterocolitica infected primary human macrophages YopM increased the level of Interleukin-10 (IL-10) mRNA and this effect required interaction of YopM with RSK and was enhanced by blocking YopM's nuclear export. We propose that the DDX3/CRM1 mediated nucleocytoplasmic shuttling of YopM determines the extent of phosphorylation of RSK in the nucleus to control transcription of immunosuppressive cytokines.

【 授权许可】

CC BY