Ribonuclease L (RNase L)

Ribonuclease L is an interferon-induced endoribonuclease that plays a central role in the innate immune response against viral infections. It is produced in an inactive form within cells but becomes activated upon binding to 2'-5'-linked oligoadenylates (2–5A), which are synthesized by OAS proteins only during viral infection when double-stranded RNA is present[1]. Upon activation—mediated by dimerization—RNase L cleaves both host and viral single-stranded RNAs preferentially at UA and UU dinucleotides[3][4]. This widespread degradation inhibits protein synthesis, suppresses viral replication, induces apoptosis or autophagy, and generates small RNA fragments that further stimulate antiviral signaling via RIG-I/MDA5 pathways[1][3]. Structurally, RNase L contains three main domains: an N-terminal ankyrin repeat domain responsible for 2–5A binding; a kinase homology domain involved in structural regulation; and a C-terminal ribonuclease domain responsible for catalytic activity[3][4]. Genetic mutations affecting its function have been linked to increased susceptibility to certain cancers such as prostate cancer[4]. Some viruses have evolved mechanisms to inhibit RNase L directly or degrade its activator molecules as part of their immune evasion strategies[5]. In vitro studies show curcumin can inhibit RNase L activity[1], but no clinically approved drugs specifically target this enzyme. Overall, Ribonuclease L is considered a key therapeutic target due to its pivotal role in antiviral defense mechanisms mediated by interferons.

Other names

2-5A-dependent ribonucleaseRNASELribonuclease L

Activation by 2'-5'-linked oligoadenylates (2–5A), leading to dimerization and activation of the enzyme for RNA cleavage at specific dinucleotides in viral and host RNA, resulting in inhibition of protein synthesis and promotion of cell death pathways such as apoptosis and autophagy. This also amplifies type I interferon responses through generation of immunostimulatory RNA fragments.