RNase L

RNase L is the acronym for ribonuclease L ( L for latent), an enzyme that is activated only under viral infection when tight binding of the inactive form of the protein occurs with a viral dsRNA consisting of the retrovirus ssRNA and its complementary strand. RNase L is present only in very small amounts during the normal cell cycle.

When interferons bind to cell receptors, the cytokine activates the transcription of approximately 300 genes to induce the antiviral activity state, including the RNase L gene (chromosome1q25.3), which encodes RNase L. Once OAS1 (2'-5'-oligoadenylate synthetase 1) is active, this synthetase converts ATP into pyrophosphate and 2'-5'-linked oligoadenylates (2-5A), which are phosphorylated at the 5'-end. 2-5 A molecules then bind to RNase L and promote its activation by dimerization. In its activated form, RNase L cleaves all RNA molecules in the cell, leading to autophagy and apoptosis. Some of the resulting RNA fragments are able to further induce IFN-β production (Birdwell LD et al. 2016).

RNase L is part of the body's immune defense, namely the "antiviral state" of the cell. When a cell is in an interferon (IFN)-inducible antiviral state, it is highly resistant to viral attack. This antiviral state is mediated in part by the 2',5'-oligoadenylate (2-5A) synthetase (OAS)/RNase L pathway. RNase L restricts viral infections by degrading viral and cellular RNA, inducing autophagy and apoptosis, and producing RNA degradation products that enhance the production of type I interferons (IFNs) via RIG-I-like receptors (Banerjee S et al. 2014).

The OAS/RNase L pathway is active against many viruses.

Note: Surprisingly, viruses have evolved in various ways to "evade this defense mechanism". For example, influenza virus A acts upstream by hiding double-stranded RNA through its NS1 protein. The murine coronavirus (mouse hepatitis virus) produced a non-structural protein 2 (NS2). This is a 2',5'-phosphodiesterase (PDE) capable of cleaving the 2',5'-oligoadenylate (2-5A) synthetase 2-5A. This antagonizes the activation of RNase L (Banerjee S et al. 2014). The fact that viral proteins have evolved to specifically antagonize RNase L highlights the importance of this particular IFN effector in virally infected cells (Drappier M et al. 2014).

RNase L has been shown to be involved in many infectious diseases. Heterozygous germline mutation in the gene encoding ribonuclease L (RNASEL; 180435) on chromosome 1q25 has been associated with hereditary prostate carcinoma-1 (HPC1)(Carpten J et al. 2002; Cher M L et al. 1996). Subsequent studies have not confirmed this association (Daugherty SE et al. 2007).

1. Banerjee S et al. (2014) Cell-type-specific effects of RNase L on viral induction of beta interferon. mBio 5:e00856-14.
2. Carpten J et al (2002) Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nature Genet 30: 181-184
3. Cher M L et al (1996) Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping. Cancer Res 56: 3091-3102
4. Daugherty SE et al (2007) RNASEL Arg462Gln polymorphism and prostate cancer in PLCO. Prostate 67:849-854.
5. Drappier M et al (2014) The OAS/RNaseL pathway and its inhibition by viruses. Virology (Montrouge) 18:264-277.
6. Xia J et al. (2019) Evidence from 40 Studies that 2 Common Single-Nucleotide Polymorphisms (SNPs) of RNASEL Gene Affect Prostate Cancer Susceptibility: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-Compliant Meta-Analysis. Med Sci Monit 25:8315-8325.