Some of the same components that process and package miRNAs also play another crucial part in the life of a cell: they serve as a powerful cell defense mechanism. In this case, the system is used to eliminate “foreign” RNA molecules—in particular, long, double-stranded RNA molecules. Such RNAs are rarely produced by normal genes, but they often serve as intermediates in the life cycles of viruses and in the movement of some transposable genetic elements. This form of RNA targeting, called RNA interference (RNAi), keeps these potentially destructive elements in check.

In the first step of RNAi, double-stranded, foreign RNAs are cut into short fragments ( ~ 22 nucleotide pairs in length) in the cytosol by a protein called Dicer—the same protein used to generate the double-stranded RNA intermediate in miRNA production. The resulting double-stranded RNA fragments, called small interfering RNAs (siRNAs), are then taken up by the same RISC proteins that carry miRNAs. The RISC discards one strand of the siRNA duplex and uses the remaining single-stranded RNA to seek and destroy complementary RNA molecules. In this way, the infected cell effectively turns the foreign RNA against itself.

At the same time, RNAi can also selectively shut off the synthesis of foreign RNAs by the host’s RNA polymerase. In this case, the siRNAs produced by Dicer are packaged into a protein complex called RITS (for RNA-induced transcriptional silencing). Using its single-stranded siRNA as a guide, the RITS complex attaches itself to complementary RNA sequences as they emerge from an actively transcribing RNA polymerase.

RNAi operates in a wide variety of organisms, including single-celled fungi, plants, and worms, indicating that it is an evolutionarily ancient defense mechanism, particularly against viral infection. In some organisms, including many plants, the RNAi defense response can spread from tissue to tissue, allowing an entire organism to become resistant to a virus after only a few of its cells have been infected. In this sense, RNAi resembles certain aspects of the adaptive immune responses of vertebrates; in both cases, an invading pathogen elicits the production of molecules—either siRNAs or antibodies—that are custom-made to inactivate the specific invader and thereby protect the host.