Life is tough. Every living thing is constantly dealing with insults that damage or disrupt homeostasis. At the cellular level these insults, or stresses, come in multiple forms: starvation, oxidative stress, heat shock, radiation damage, and infection. In response to these stresses, organisms have evolved numerous mechanisms to promote survival. Broadly speaking, an insult stimulates various signaling cascades that alter gene expression in the cell.

One way this is achieved is through the “turning on” of transcription factors. One such transcription factor is FOXO, which is activated under many types of stress, both metabolic and environmental. Another way gene expression can be accomplished is the post-transcriptional control of gene expression. An important player of post-transcriptional control is the small RNA pathways composed of the RNA interference (RNAi), micro RNA (miRNA), and PIWI RNA (piRNA) branches. In a recent article from the Marr lab titled “FOXO regulates RNA interference in Drosophila and protects from RNA virus infection”, published in PNAS this November, the authors identify a new connection between both the transcriptional and small RNA mediated post-transcriptional mechanisms that respond to stress.

RNAi efficiency is enhanced in a dFOXO-dependent manner. For full explanations, see Fig. 2 in Spellberg & Marr (2015)

Using Drosophila as a model system, the authors identify FOXO as a transcription factor that regulates important genes in the small RNA pathways in response to stress. This is the first transcription factor identified to control these genes. Despite being a hot and competitive field for over 15 years, work in small RNA pathways had yet to reveal the transcriptional regulation of the core protein machinery that are involved in small RNA biogenesis and utilization. Under stress conditions, FOXO directly binds the promoters of core small RNA pathway genes, such as Ago1, Ago2, and Dicer 2, leading to increases in their expression. As one might expect, this is followed by an increase in RNAi efficiency and post-transcriptional control of gene expression.

A known physiological role for RNAi is to fight off viral infections as part of an innate immune response. The authors find that FOXO is activated by viral infection to promote this anti-viral response. In addition, animals deleted for the FOXO gene are more susceptible to a viral infection. Theses results are consistent with the notion that virally-activated FOXO stimulates RNAi gene transcription as a mechanism to enhance viral immunity.

Finally, the work in this paper identifies integration between metabolic and stress signaling and the innate immune response, with FOXO serving the bridge. There is evidence that acute stress can confer a protective effect against infection in humans. If the identified role of FOXO is conserved, perhaps it can be utilized therapeutically.

Spellberg MJ, Marr MT, 2nd. FOXO regulates RNA interference in Drosophila and protects from RNA virus infection. Proc Natl Acad Sci U S A. 2015