The silencing of ets-4 mRNA relies on the functional cooperation between REGE-1/Regnase-1 and RLE-1/Roquin-1.

Regnase-1 is an evolutionarily conserved endoribonuclease. It degrades diverse mRNAs important for many biological processes including immune homeostasis, development and cancer. There are two competing models of Regnase-1-mediated mRNA silencing. One model postulates that Regnase-1 works together with another RNA-binding protein, Roquin-1, which recruits Regnase-1 to specific mRNAs. The other model proposes that the two proteins function separately. Studying REGE-1, the Caenorhabditis elegans ortholog of Regnase-1, we have uncovered its functional relationship with RLE-1, the nematode counterpart of Roquin-1. While both proteins are essential for mRNA silencing, REGE-1 and RLE-1 appear to associate with target mRNA independently of each other. Thus, although the functional interdependence between REGE-1/Regnase-1 and RLE-1/Roquin-1 is conserved, the underlying mechanisms may display species-specific variation, providing a rare perspective on the evolution of this important post-transcriptional regulatory mechanism.

Structure of bacterial regulatory RNAs determines their performance in competition for the chaperone protein Hfq.

Bacterial regulatory RNAs require the chaperone protein Hfq to enable their pairing to mRNAs. Recent data showed that there is a hierarchy among sRNAs in the competition for access to Hfq, which could be important for the tuning of sRNA-dependent translation regulation. Here, seven structurally different sRNAs were compared using filter-based competition assays. Moreover, chimeric sRNA constructs were designed to identify structure elements important for competition performance. The data showed that besides the 3'-terminal oligouridine sequences also the 5'-terminal structure elements of sRNAs were essential for their competition performance. When the binding of sRNAs to Hfq mutants was compared, the data showed the important role of the proximal and rim sites of Hfq for the binding of six out of seven sRNAs. However, ChiX sRNA, which was the most efficient competitor, bound Hfq in a unique way using the opposite-distal and proximal-faces of this ring-shaped protein. The data indicated that the simultaneous binding to the opposite faces of Hfq was enabled by separate adenosine-rich and uridine-rich sequences in the long, single-stranded region of ChiX. Overall, the results suggest that the individual structural composition of sRNAs serves to tune their performance to different levels resulting in a hierarchy of sRNAs in the competition for access to the Hfq protein.

The emerging roles of tRNAs and tRNA-derived fragments during aging: Lessons from studies on model organisms.

Aging is a gradual decline of various functions of organisms resulting in diminished abilities to protect against the environmental damage and reinforce the physiological harmony. Age-related functional declines have been thought to be passive and not regulated. However, studies on numerous model organisms, from yeast to mammals, exposed that the mechanisms of lifespan regulation are remarkably conserved throughout the evolution. Following the pioneering genetic studies in C. elegans, it has been shown that the genes related to the longevity are conserved in yeast, flies and mice. For a long time, tRNAs have been only considered as molecules transporting amino acids to the ribosome during translation. Nonetheless, it has become apparent from many biological studies that tRNAs are entangled in a variety of physiological and pathological processes. This review focuses on the emerging roles of tRNA-associated processes in aging and lifespan of model organisms. More specificaly, we present a summary on the importance of tRNA metabolism, epitranscriptome and possible roles of tRNA-derived fragments in aging and lifespan regulation. Better understanding of the basic mechanisms of aging could lead to the development of new diagnostics and treatments for aging-related diseases.

Ferritin-mediated iron detoxification promotes hypothermia survival in Caenorhabditis elegans and murine neurons.

How animals rewire cellular programs to survive cold is a fascinating problem with potential biomedical implications, ranging from emergency medicine to space travel. Studying a hibernation-like response in the free-living nematode Caenorhabditis elegans, we uncovered a regulatory axis that enhances the natural resistance of nematodes to severe cold. This axis involves conserved transcription factors, DAF-16/FoxO and PQM-1, which jointly promote cold survival by upregulating FTN-1, a protein related to mammalian ferritin heavy chain (FTH1). Moreover, we show that inducing expression of FTH1 also promotes cold survival of mammalian neurons, a cell type particularly sensitive to deterioration in hypothermia. Our findings in both animals and cells suggest that FTN-1/FTH1 facilitates cold survival by detoxifying ROS-generating iron species. We finally show that mimicking the effects of FTN-1/FTH1 with drugs protects neurons from cold-induced degeneration, opening a potential avenue to improved treatments of hypothermia.

Bacterial Chaperone Protein Hfq Facilitates the Annealing of Sponge RNAs to Small Regulatory RNAs.

Bacterial small RNAs (sRNAs) in association with the chaperone protein Hfq regulate the expression of many target mRNAs. Since sRNAs' action is crucial to engendering a response to changing environmental conditions, their activity needs to be regulated. One such mechanism occurs at the post-transcriptional level and involves sponge RNAs, which sequester sRNAs affecting their regulatory output. Both types of RNAs were identified on Hfq, but it is not known how Hfq interacts with RNA sponges and stimulates their base-pairing with sRNAs. Here, we used biochemical methods to demonstrate that sponge RNAs resemble sRNAs by their structure and their modes of Hfq binding. Hfq facilitates the annealing of AgvB and 3'ETSleuZ sponge RNAs to targeted sRNAs: GcvB and RybB, respectively, and each surface of the protein plays a particular role in the process. Moreover, we found that the efficiency of sponge RNA interactions with sRNAs can be improved; therefore, we propose that natural RNA sponges might not sequester sRNAs optimally.

Structural and functional relationship of mammalian and nematode ferritins.

Ferritin is a unique buffering protein in iron metabolism. By storing or releasing iron in a tightly controlled manner, it prevents the negative effects of free ferrous ions on biomolecules in all domains of life - from bacteria to mammals. This review focuses on the structural features and activity of the ferritin protein family with an emphasis on nematode ferritins and the similarities in their biological roles with mammalian ferritins. The conservative characteristic of the ferritin family across the species originates from the ferroxidase activity against redox-active iron. The antioxidative function of these proteins translates into their involvement in a wide range of important biological processes, e.g., aging, fat metabolism, immunity, anticancer activity, and antipathogenic activity. Moreover, disturbances in ferritin expression lead to severe iron-associated diseases. Research on the Caenorhabditis elegans model organism may allow us to better understand the wide spectrum of mechanisms involving ferritin activity.