Abstract
As part of their innate immune response against viral infections, mammals activate the expression of type I interferons to prevent viral replication and dissemination. An antiviral RNAi-based response can be also activated in mammals, suggesting that several mechanisms can co-occur in the same cell and that these pathways must interact to enable the best antiviral response. Here, we will review how the classical type I interferon response and the recently described antiviral RNAi pathways interact in mammalian cells. Specifically, we will uncover how the small RNA biogenesis pathway, composed by the nucleases Drosha and Dicer can act as direct antiviral factors, and how the type-I interferon response regulates the function of these. We will also describe how the factors involved in small RNA biogenesis and specific small RNAs impact the activation of the type I interferon response and antiviral activity. With this, we aim to expose the complex and intricate network of interactions between the different antiviral pathways in mammals.
Highlights
With the exception of TLR3, which is specialized in Double-stranded RNAs (dsRNAs) recognition [21], Toll-like receptors (TLRs) signaling depends on the adaptor protein myeloid differentiation primary response 88 (MyD88) [20]
The presence of cytoplasmic virus-derived RNA is detected by a family of receptors called RIG-I-like receptors (RLRs), which include retinoic-acid-inducible protein 1 (RIG-I), melanoma-differentiation-associated gene 5 (MDA5), laboratory of genetics physiology 2 (LGP2), and signals through the mitochondrial antiviral-signaling protein (MAVS)
This paper showed that knocking down Dicer by shRNAs might be efficient, but not sufficient to completely impair miRNA biogenesis
Summary
Interferons (IFNs) are the major cytokines expressed during the innate immune response against invading pathogens, such as viruses, bacteria, fungi, and parasites. In the context of viral infections, the type I IFN response is activated by sensing the presence of invading viruses These pathogens pose a particular challenge for detection by the innate immune system due to their small size and constantly evolving surface protein repertoire, host cells have developed the ability to recognize virus-specific nucleic acid signatures. Secreted type I IFN proteins act in an auto- and paracrine fashion by binding to the heterodimeric type I IFN receptors, IFNAR1 and 2, on the surface of the infected and neighboring cells This initiates the janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway that activates a second transcriptional response of around 500 IFN-stimulated genes (ISGs), which establishes the antiviral state [17,18]. We focus on the mechanisms that cells use to detect invasion by viruses
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