The RNA helicase DDX3X is an essential mediator of innate antimicrobial immunity.

Roland Tschismarov,Mathias Müller,Katrin Fischer,Sandra Westermayer,Daniel Szappanos,Fabian Kallinger,Josef M. Penninger,Veronika Sexl,Thomas Perlot,Caroline Lassnig,Maria Novatchkova,Igor Eric Brodsky,Keiryn L. Bennett,Michelle Foong-Sobis,Ekaterini Platanitis,Thomas Decker

doi:10.1371/journal.ppat.1007397

Abstract

DExD/H box RNA helicases, such as the RIG-I-like receptors (RLR), are important components of the innate immune system. Here we demonstrate a pivotal and sex-specific role for the heterosomal isoforms of the DEAD box RNA helicase DDX3 in the immune system. Mice lacking DDX3X during hematopoiesis showed an altered leukocyte composition in bone marrow and spleen and a striking inability to combat infection with Listeria monocytogenes. Alterations in innate immune responses resulted from decreased effector cell availability and function as well as a sex-dependent impairment of cytokine synthesis. Thus, our data provide further in vivo evidence for an essential contribution of a non-RLR DExD/H RNA helicase to innate immunity and suggest it may contribute to sex-related differences in resistance to microbes and resilience to inflammatory disease.

Highlights

Upon infection, germline-encoded pattern recognition receptors (PRRs) located on the surface of cells, in endosomal compartments and throughout the cytosol initiate an array of signaling cascades that culminate in the production of type I interferons (IFN-I), pro-inflammatory cytokines and chemokines
Homozygous female offspring (Ddx3xfl/fl Vav-iCre) was not obtained. This emphasizes an important role of DDX3 isoforms in hematopoiesis and suggests that the Y chromosome contains genes that compensate for DDX3X deficiency to the point of ensuring survival and an absence of overt phenotypic abnormalities of unchallenged animals
DDX3X was able to enhance the activity of an NFκB reporter gene (Fig 1F), suggesting its impact on innate immune responses may extend beyond the IRF3/7 pathway

Summary

Introduction

Germline-encoded pattern recognition receptors (PRRs) located on the surface of cells, in endosomal compartments and throughout the cytosol initiate an array of signaling cascades that culminate in the production of type I interferons (IFN-I), pro-inflammatory cytokines and chemokines. These cytokines establish an inflammatory response and an antimicrobial state restraining the spread of the infectious agent. Male embryos with epiblast-restricted DDX3X deletion die around E11.5 with widespread occurrence of apoptotic cells and expression of DNA damage markers [10] This is most likely a direct consequence of a disturbed cell cycle in embryonic tissue lacking DDX3X. This view is further supported by a study investigating the role of DDX3X in early mouse development using siRNA-mediated knockdown [11]

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Results

Conclusion