- RNase L is an interferon-induced endoribonuclease that plays a key role in the mammalian innate immune response, particularly in antiviral defense. It is a component of the 2-5A system, a cellular pathway activated by type I interferons in response to viral infections. The enzyme is produced in a latent form and remains inactive in uninfected cells. Upon viral infection, double-stranded RNA (dsRNA), which is often produced during viral replication, activates 2′,5′-oligoadenylate synthetase (OAS) enzymes. These enzymes convert ATP into short 2′,5′-linked oligoadenylates (2-5A), which are unique signaling molecules not typically found in cells.
- The activation of RNase L depends on these 2-5A molecules. When sufficient levels of 2-5A are present, they bind to RNase L, triggering its dimerization, which is required for enzymatic activity. Once activated, RNase L cleaves single-stranded RNA (ssRNA), targeting both viral RNA and host cellular RNA. This leads to degradation of viral genomes, limiting virus replication, and also shuts down host protein synthesis, further inhibiting viral propagation. Moreover, the RNA fragments generated by RNase L activity can act as signals that enhance immune responses by activating pattern recognition receptors such as RIG-I and MDA5.
- RNase L activity is also linked to the induction of apoptosis in virus-infected cells. By degrading critical host RNAs, RNase L promotes cellular stress responses and can trigger programmed cell death, which helps prevent the spread of viruses. In addition to its role in antiviral defense, RNase L has been implicated in broader biological processes such as regulation of cell proliferation and tumor suppression. Mutations in the RNASEL gene have been associated with increased susceptibility to prostate cancer, and deregulation of its activity has been linked to chronic inflammatory and autoimmune conditions.
- Due to its central role in host defense and RNA metabolism, RNase L is of significant biomedical interest. Strategies to modulate RNase L activity are being investigated for therapeutic purposes. Enhancing its function could be beneficial in developing antiviral therapies, while controlling its activation may be useful in treating conditions where excessive RNA degradation leads to tissue damage or inflammation.
- In summary, RNase L is a critical effector of the interferon-mediated antiviral response. Its activation through 2-5A molecules enables it to degrade RNA, suppress viral replication, and trigger immune signaling and apoptosis. As a ribonuclease with far-reaching implications in immunity, cancer, and inflammation, RNase L remains an important focus of research in molecular and clinical biology.
