The molecular language of RNA 5' ends: guardians of RNA identity and immunity.

RNA caps are deposited at the 5' end of RNA polymerase II transcripts. This modification regulates several steps of gene expression, in addition to marking transcripts as self to enable the innate immune system to distinguish them from uncapped foreign RNAs, including those derived from viruses. Specialized immune sensors, such as RIG-I and IFITs, trigger antiviral responses upon recognition of uncapped cytoplasmic transcripts. Interestingly, uncapped transcripts can also be produced by mammalian hosts. For instance, 5'-triphosphate RNAs are generated by RNA polymerase III transcription, including tRNAs, Alu RNAs, or vault RNAs. These RNAs have emerged as key players of innate immunity, as they can be recognized by the antiviral sensors. Mechanisms that regulate the presence of 5'-triphosphates, such as 5'-end dephosphorylation or RNA editing, prevent immune recognition of endogenous RNAs and excessive inflammation. Here, we provide a comprehensive overview of the complexity of RNA cap structures and 5'-triphosphate RNAs, highlighting their roles in transcript identity, immune surveillance, and disease.

Sensing of transposable elements by the antiviral innate immune system.

Around half of the genome in mammals is composed of transposable elements (TEs) such as DNA transposons and retrotransposons. Several mechanisms have evolved to prevent their activity and the detrimental impact of their insertional mutagenesis. Despite these potentially negative effects, TEs are essential drivers of evolution, and in certain settings, beneficial to their hosts. For instance, TEs have rewired the antiviral gene regulatory network and are required for early embryonic development. However, due to structural similarities between TE-derived and viral nucleic acids, cells can misidentify TEs as invading viruses and trigger the major antiviral innate immune pathway, the type I interferon (IFN) response. This review will focus on the different settings in which the role of TE-mediated IFN activation has been documented, including cancer and senescence. Importantly, TEs may also play a causative role in the development of complex autoimmune diseases characterised by constitutive type I IFN activation. All these observations suggest the presence of strong but opposing forces driving the coevolution of TEs and antiviral defence. A better biological understanding of the TE replicative cycle as well as of the antiviral nucleic acid sensing mechanisms will provide insights into how these two biological processes interact and will help to design better strategies to treat human diseases characterised by aberrant TE expression and/or type I IFN activation.

ILF3 contributes to the establishment of the antiviral type I interferon program.

Upon detection of viral infections, cells activate the expression of type I interferons (IFNs) and pro-inflammatory cytokines to control viral dissemination. As part of their antiviral response, cells also trigger the translational shutoff response which prevents translation of viral mRNAs and cellular mRNAs in a non-selective manner. Intriguingly, mRNAs encoding for antiviral factors bypass this translational shutoff, suggesting the presence of additional regulatory mechanisms enabling expression of the self-defence genes. Here, we identified the dsRNA binding protein ILF3 as an essential host factor required for efficient translation of the central antiviral cytokine, IFNB1, and a subset of interferon-stimulated genes. By combining polysome profiling and next-generation sequencing, ILF3 was also found to be necessary to establish the dsRNA-induced transcriptional and translational programs. We propose a central role for the host factor ILF3 in enhancing expression of the antiviral defence mRNAs in cellular conditions where cap-dependent translation is compromised.

Inhibition of Microprocessor Function during the Activation of the Type I Interferon Response.

Type I interferons (IFNs) are central components of the antiviral response. Most cell types respond to viral infections by secreting IFNs, but the mechanisms that regulate correct expression of these cytokines are not completely understood. Here, we show that activation of the type I IFN response regulates the expression of miRNAs in a post-transcriptional manner. Activation of IFN expression alters the binding of the Microprocessor complex to pri-miRNAs, reducing its processing rate and thus leading to decreased levels of a subset of mature miRNAs in an IRF3-dependent manner. The rescue of Microprocessor function during the antiviral response downregulates the levels of IFN-ß and IFN-stimulated genes. All these findings support a model by which the inhibition of Microprocessor activity is an essential step to induce a robust type I IFN response in mammalian cells.

Genetic variation and RNA structure regulate microRNA biogenesis.

MiRNA biogenesis is highly regulated at the post-transcriptional level; however, the role of sequence and secondary RNA structure in this process has not been extensively studied. A single G to A substitution present in the terminal loop of pri-mir-30c-1 in breast and gastric cancer patients had been previously described to result in increased levels of mature miRNA. Here, we report that this genetic variant directly affects Drosha-mediated processing of pri-mir-30c-1 in vitro and in cultured cells. Structural analysis of this variant revealed an altered RNA structure that facilitates the interaction with SRSF3, an SR protein family member that promotes pri-miRNA processing. Our results are compatible with a model whereby a genetic variant in pri-mir-30c-1 leads to a secondary RNA structure rearrangement that facilitates binding of SRSF3 resulting in increased levels of miR-30c. These data highlight that primary sequence determinants and RNA structure are key regulators of miRNA biogenesis.

Patrón de alimentación e incorporación de alimentos complementarios en lactantes de una población de bajos recursos / Feeding pattern and incorporation of complementary foods in infants from a low- income population

In Argentina the information about the characteristics of complementary feeding is scarce. The objective of the present study was to determine the age of incorporation and type of complementary foods in the diet of infants from a population of low economic resources. The study was carried out at the Forres District Hospital, Santiago del Estero, Argentina, using a structured questionnaire. Breastfeeding mothers were interrogated during the children's periodic control visits. A total of 240 surveys at 5, 6 and 7 months post-partum were made. The average age of incorporation of foods was of 4.4 months. The first introduced foods were purée (potato and pumpkin, with broth or soup), soup (with wheat grits) and apple. The percentage of children consuming some type of gruel at 5 months was of 51%. At 7 months, 94% consumed gruels and 62.5% had milk bottles. About 40% ate the family stew (vegetables, noodles and meat) and 30%, a "mate" (Ilexparaguariensis) infusion with bread. An early incorporation of foods with inadequate energy and nutrients densities was observed. There was also an early ingestion of gluten and a high proportion of cow's milk consumption. This situation could affect the normal development of these children.

En Argentina existe escasa información sobre las características de la alimentación complementaria. El objetivo del presente trabajo fue determinar la edad de inicio y tipo de alimentos complementarios incorporados en la dieta de lactantes, en una población de escasos recursos socio-económicos. El estudio se realizó en el Hospital Distrital de Forres, Santiago del Estero, utilizando una encuesta estructurada. Las madres en etapa de lactancia fueron interrogadas durante las visitas periódicas de control de sus hijos. Se realizaron 240 encuestas, a los 5, 6 y 7 meses post-parto. La edad promedio de incorporación de alimentos fue 4,4 meses. Los primeros alimentos incorporados fueron: puré (papa y zapallo, con caldo o sopa), sopa (con sémola) y manzana. El 51% de los niños consumía algún tipo de papilla a los 5 meses. A los 7 meses, el 94% consumían papillas y el 62,5% tomaban mamadera. El 40% comía el guiso familiar (verduras, fideos y carne) y el 30%, mate cocido con pan. Se observó incorporación temprana de alimentos con densidad energética y de nutrientes inadecuadas, ingesta precoz de gluten y elevada proporción de consumo de leche de vaca. Esta situación podría afectar el normal desarrollo de los niños de la población estudiada.

Hormonal regulation of microRNA biogenesis.

In this issue of Molecular Cell, Yamagata et al. (2009) provide insight into the complex posttranscriptional regulation of miRNA biogenesis by showing that the processing of a subset of miRNAs is inhibited by the estrogen receptor.