RNA interference: The molecular immune system

Abstract

SummaryIntroduction of double-stranded RNA (dsRNA) into cells expressing a homologous gene triggers RNA interference (RNAi), or RNA-based gene silencing (RBGS). The dsRNA degrades corresponding host mRNA into small interfering RNAs (siRNAs) by a protein complex containing Dicer. siRNAs in turn are incorporated into the RNA-induced silencing complex (RISC) that includes helicase, RecA, and exo-and endo-nucleases as well as other proteins. Following its assembly, the RISC guides the RNA degradation machinery to the target RNAs and cleaves the cognate target RNA in a sequence-specific, siRNA-dependent manner. RNAi has now been documented in a wide variety of organisms, including plants, fungi, flies, worms, and more recently, higher mammals. In eukaryotes, dsRNA directed against a range of viruses (i.e., HIV-1, RSV, HPV, poliovirus and others) and endogenous genes can induce sequence-specific inhibition of gene expression. In invertebrates, RNAi can be efficiently triggered by either long dsRNAs or 21-to 23-nt-long siRNAs. However, in jawed vertebrates, dsRNA longer than 30 bp can induce interferon and thus trigger undesirable side effects instead of initiating RNAi. siRNAs have been shown to act as potent inducers of RNAi in cultured mammalian cells. Many investigators have suggested that siRNAs may have evolved as a normal defense against endogenous and exogenous transposons and retroelements. Through a combination of genetic and biochemical approaches, some of the mechanisms underlying RNAi have been described. Recent data in C. elegans shows that two homologs of siRNAs, microRNAs (miRNAs) and tiny noncoding RNAs (tncRNAs) are endogenously expressed. However, many aspects of RNAi-induced gene silencing, including its origins and the selective pressures which maintain it, remain undefined. Its evolutionary history may pass through the more primitive immune functions of prokaryotes involving restriction enzymes that degrade plasmid DNA molecules that enter bacterial cells. RNAi has evolved further among eukaryotes, in which its wide distribution suggests early origins. RNAi seems to be involved in a variety of regulatory and immune functions that may differ among various kingdoms and phyla. We present here proposed mechanisms by which RBGS protects the host against endogenous and exogenous transposons and retroelements. The potential for therapeutic application of RBGS technology in treating viral infections such as HIV is also discussed.

Grass carp reovirus activates RNAi pathway in rare minnow, Gobiocypris rarus

“…However, in jawed vertebrates, dsRNA longer than 30 bp can induce the interferon (IFN) pathway and thus triggers undesirable side effects instead of initiating RNAi. siRNAs have been shown to act as potent inducers of RNAi in cultured mammalian cells (Bagasra and Prilliman, 2004).…”

Endo-siRNA deficiency results in oocyte maturation failure and apoptosis in porcine oocytes

“…Why does endo-siRNA deficiency cause disordered chromosomes and spindle morphology? The explanation could be that centromeres are composed of repetitive sequences and endo-siRNAs are involved in silencing of repetitive sequences (Bagasra and Prilliman 2004;Ekwall 2007;Banisch et al 2012;Fukagawa and Earnshaw 2014). The loss of endo-siRNAs may activate heterochromatin repetitive sequences and prevent centromeres from connecting to microtubules (Kanellopoulou et al 2005;Ekwall 2007;Saito and Siomi 2010;Castel and Martienssen 2013;Li 2014).…”

Use of Flaviviral genetic fragments as a potential prevention strategy for HIV-1 Silencing

“…Sustained research from various laboratories suggests how miRNAs control RNA and DNA viral replication; invading viruses can be recognized by cellular miRNAs, which can target specific genetic material [30]. A substantial part of eukaryotic genomes is made up of retroelements (RE) (e.g., lentiviruses, retroviruses, retrotransposons, and transposons).…”