RNASEL
Description
The RNASEL (ribonuclease L) is a protein-coding gene located on chromosome 1.
Ribonuclease L, or RNase L (for latent), also known as ribonuclease 4 or 2'-5' oligoadenylate synthetase-dependent ribonuclease, is an interferon (IFN)-induced ribonuclease that, upon activation, destroys all RNA within the cell (both cellular and viral). RNase L is an enzyme encoded by the RNASEL gene in humans. This gene encodes a component of the interferon-regulated 2'-5' oligoadenylate (2'-5'A) system, which plays a role in the antiviral and antiproliferative effects of interferons. RNase L is activated by dimerization, which occurs upon 2'-5'A binding, leading to the cleavage of all RNA in the cell. This can activate MDA5, an RNA helicase involved in interferon production.
RNase L is present in very low amounts during the normal cell cycle. When interferon binds to cell receptors, it activates the transcription of approximately 300 genes to establish an antiviral state. Among the enzymes produced is RNase L, which is initially inactive. A set of transcribed genes encodes 2'-5' Oligoadenylate Synthetase (OAS). The transcribed RNA is then spliced and modified in the nucleus before reaching the cytoplasm and being translated into an inactive form of OAS. The location of OAS in the cell and the length of the 2'-5' oligoadenylate depend on the post-transcriptional and post-translational modifications of OAS. OAS is only activated during a viral infection, when the inactive form of the protein binds tightly to viral dsRNA, consisting of the retrovirus' ssRNA and its complementary strand.
RNASEL is an endoribonuclease that plays a critical role in the interferon (IFN)-mediated antiviral response. In cells treated with IFN or infected with viruses, RNASEL exerts its antiviral effects through a variety of mechanisms, including:
- Direct cleavage of single-stranded viral RNAs
- Inhibition of protein synthesis by degrading rRNA
- Induction of apoptosis
- Activation of other antiviral genes
RNASEL-mediated apoptosis is triggered by a JNK-dependent stress response pathway that leads to the release of cytochrome c from mitochondria and caspase-dependent apoptosis. This suggests that activation of RNASEL can eliminate virus-infected cells under certain conditions. In the interplay between autophagy and apoptosis, RNASEL is thought to induce autophagy as an initial stress response to small double-stranded RNA. At later stages of prolonged stress, RNASEL activates caspase-dependent proteolytic cleavage of BECN1, which terminates autophagy and promotes apoptosis. RNASEL may also play a central role in regulating mRNA turnover. It cleaves the 3' ends of UpNp dimers, with a preference for UU and UA sequences, generating discrete products ranging from 4 to 22 nucleotides in length.
RNASEL is also known as PRCA1, RNS4.
