The Role Of DDX3X In The Immune System

The innate immune system establishes a first-line defense against invading pathogenic microorganisms. The pathogens are sensed by dedicated antigen receptors. These receptors subsequently emit signals that reprogram cells of the immune system, preparing them for combat. Enabling cells to increase their immunological performance requires them to turn on sometimes hundreds of genes and repress others whose products are not needed.

Enzymes belonging to the large family of RNA helicases function in many aspects of RNA metabolism such as processing, transport, and translation of the genetic code into proteins. In addition, some RNA helicases were identified as sensors of pathogen RNA, allowing the immune system to detect pathogens replicating inside cells such as viruses or certain bacteria. Again other helicases are used by cells of the immune system to transduce activating signals or to enhance the synthesis of mRNAs for antimicrobial effector mechanisms. RNA helicase DDX3X falls into this latter category of RNA helicases. Besides its classical functions in RNA metabolism our work showed that the enzyme increases the synthesis of immune mediators called interferons, molecules that communicate a state of infection between cells. Based on this finding, we decided to eliminate the gene for DDX3X in mice and study the consequences for immune responses against microbial pathogens.

Deletion of the DDX3X gene in all mouse tissues led to embryonic lethality, most likely a consequence of the important role of the enzyme in basic RNA metabolism. It was possible, however, to selectively remove the DDX3X gene in the cells responsible for the generation of blood leukocytes. Since cells of the immune system derive from the same process, hematopoiesis, that generates the cells of the blood, DDX3X was now lacking in the entire immune system. Surprisingly, mice with a DDX3X-less immune system survived a viral infection just like normal mice.

In contrast, such mice were highly vulnerable against infection with a bacterial pathogen, Listeria monocytogenes. This microorganism is the causative agent for a food-borne disease called Listeriosis in humans. Like viruses, Listeria monocytogenes multiplies inside cells of its host’s body, including cells belonging to the immune system. For efficient removal of Listeria, such cells must be activated. We found that this process required the presence of DDX3X. Effector cells were not able to properly switch on antimicrobial genes and to produce the immune mediators required for efficient elimination of bacteria in absence of DDX3X.

An additional and very interesting facet of our analysis of DDX3X function is its sex-specific activity in the immune system. As its name implies, the DDX3X gene is located on the X-chromosome, meaning that females have two copies whereas males have one. On the other hand, the male genome includes a highly related gene, DDX3Y, on the Y-chromosome. Deletion of DDX3X in females, therefore, leaves them without any DDX3 whereas males still have their Y-chromosomal DDX3Y.

Our study shows that part of the DDX3X functions can be carried out by DDX3Y. Therefore, females lacking DDX3X in cells that generate the immune system and all blood leukocytes are not viable, but males survive due to DDX3Y. Likewise, when we deleted the DDX3X gene in cells derived from females and challenged these cells with bacteria they coped worse with infection than cells derived from male mice and similarly lacking a functional copy of DDX3X.

In summary, our study demonstrates an important function of DDX3X in the immune system that is more pronounced in females due to the absence of DDX3Y. DDX3X might be one determinant of differences between sexes in immune responses underlying antimicrobial defense or autoimmunity.