FOXO links stress to the innate immune response in flies

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.

Screen Shot 2015-11-16 at 9.22.43 AM

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

Sprout Grant Winners Announced

Winners of the 2013 Sprout Grant competition held by the Brandeis Office of Technology and Licensing have been announced. Sprout grants support research that is “novel, patentable and [has] commercial potential“, and encourage students to think about new and different ways to apply their basic science for practical good. Each team applying for a grant must be led by a Brandeis student or postdoc (noted in asterisks below), who were responsible for presenting their proposals to the review panel.

Teams that received funding.

  • Marcus Long (*), Ann Lawson, Lior Rozhansky ’15, and Liz Hedstrom: $20,000 to develop novel inhibitors of deubiquitinating enzymes;
  • Michael Heymann (*), Achini Opathalage, Dongshin Kim, and Seth Fraden: $5,500 for its development of CrystalChip;
  • Michael Spellberg (*), Calla Olson, Marissa Donovan, and Mike Marr: $10,000 to develop a tool to purify Calmodulin-tagged recombinant proteins;
  • Julian Eskin (*) and Bruce Goode: $2,000 for work on a rapid and efficient kit to purify actin;
  • Eugene Goncharov ’13 (*), Yuval Galor ’15,  and Alex Bardasu ’15: $2,500 towards development of their iPhone app LineSaver, which collects data on local hotspots and gives users an estimated wait-time for restaurants, clubs and tourist attractions.

You can read more at BrandeisNOW

More science

We’ve all been busy this spring writing grants and teaching courses and doing research and graduating(!), so lots of publications snuck by that we didn’t comment on. Here’s a few I think that might be interesting to our readers.

  • From Chris Miller‘s lab, bacterial antiporters do act as “virtual proton efflux pumps”:
  • nsrv2Are ninja stars responsible for controlling actin disassembly? Seems like the Goode lab might think so.
    • Chaudhry F, Breitsprecher D, Little K, Sharov G, Sokolova O, Goode BL. Srv2/cyclase-associated protein forms hexameric shurikens that directly catalyze actin filament severing by cofilin. Mol Biol Cell. 2013;24(1):31-41.
  • What do you get from statistical mechanics of self-propelled particles? The Hagan and Baskaran groups team up to find out.
  • From John Lisman and Ole Jensen (PhD ’98), thoughts about what the theta and gamma rhythms in the brain encode
  • From Mike Marr‘s lab, studeies using genome-wide nascent sequencing to understand how transcrption bursting is controlled in eukaryotic cells
  • From the Lau and Sengupta labs, RNAi pathways contribute to long term plasticity in worms that have gone through the Dauer stage
    • Hall SE, Chirn GW, Lau NC, Sengupta P. RNAi pathways contribute to developmental history-dependent phenotypic plasticity in C. elegans. RNA. 2013;19(3):306-19.
  • Can nanofibers selectively disrupt cancer cell types? Early results from Bing Xu‘s group.
    • Kuang Y, Xu B. Disruption of the Dynamics of Microtubules and Selective Inhibition of Glioblastoma Cells by Nanofibers of Small Hydrophobic Molecules. Angew Chem Int Ed Engl. 2013.

2012 Rosenstiel Award Recipient, Dr. Nahum Sonenberg

2012 Rosenstiel Award Lecture
Thursday, March 29, 2012, 4:00 PM
Gerstanzang 123

The 2012 Rosenstiel award winner, Dr. Nahum Sonenberg of McGill University, is a well-deserving recipient of this honor. Dr. Sonenberg received his Ph.D. in 1976 at the Weizman Institute of Science.  He then worked with Aaron Shatkin, where he discovered the translation initiation factor responsible for binding the 5’ cap of mRNA, eukaryotic Initiation Factor 4E (eIF4E); He has studied translation ever since.  Although his lab focuses on understanding how the cell achieves precise control of translation initiation, this line of investigation has led to discoveries affecting a wide variety of systems.  His lab has made key discoveries in cancer, obesity, virology, memory consolidation and how translation control plays a role in regulating these disparate processes.

In 1988, the Sonenberg lab made the groundbreaking discovery (Nature 1988, that the uncapped viral mRNA from poliovirus recruits the ribosome to internal regions of the 5’ untranslated region (UTR).  These sites have since been renamed internal ribosomal entry sites (IRESs). This finding was exciting since eukaryotic translation initiation typically requires the 5’ cap on an mRNA for eIF4E binding which subsequently recruits translation initiation machinery.  Until this time, the only mechanism of translation initiation was through the binding of eIF4E to the 5’ cap of mRNAs.  Sonenberg’s discovery that some mRNA has a mechanism to bypass the need for eIF4E binding and thereby avoiding translation control mechanisms started a new line of investigation in the translation field.  Along with discovering IRESs, this paper established an in vitro and an in vivo assay to study cap-independent translation initiation.  These assays are still used widely to test for IRES activity of mRNA UTRs.

Since that initial discovery, it has been found that many viruses contain IRES sequences in the UTR of mRNA that direct translation of viral proteins.  Some viruses, including poliovirus, are able to hijack eukaryotic translation machinery by cleaving factors necessary for canonical cap-dependent translation initiation, but dispensable for IRES translation. In this way, viral mRNAs are able to outcompete eukaryotic mRNAs for ribosome binding and in many cases become the most abundant transcript being translated.

Since the discovery of viral IRESs, many labs, including the Sonenberg lab, have discovered that some cellular genes also use IRESs to bypass the typical translation initiation control mechanisms. These genes are capable of translating even when the cell is actively shutting down translation.  One such cellular IRES-containing mRNA is the insulin receptor message, the IRES I study in the Marr lab.  Using assays similar to those first used in the 1988 paper published by the Sonenberg lab, I am exploring the necessity for the various initiation factors and IRES sequences required for efficient translation of insulin receptor in Drosophila melanogaster and mammalian cells.

The discovery that Dr. Sonenberg made in 1988 is only one example of the elegant research his lab has produced and continues to pursue.

Drosha and Pasha

No, this isn’t a Russian short story.

Lead authors postdoc alum Sebastian Kadener and Mol Cell Biol graduate student Joe Rodriguez and their coworkers used tiling arrays to look for targets of the enzyme Drosha in “Genome-wide identification of targets of the drosha–pasha/DGCR8 complex”, a paper recently published in the journal RNA. Drosha is a type III RNAse that is involved in the processing of  miRNAs. This paper demonstrates for first time that this enzyme is not only involved in miRNA processing, but can also process mRNAs.  Interestingly, the best example of an mRNA processed by Drosha is the mRNA that encodes another miRNA processing enzyme, the protein Pasha. As this is a partner of Drosha (the two proteins work together), the findings suggest that  there is a feedback loop that controls the abundance of the miRNA processing machinery and probably the abundance of miRNAs themselves.

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