The OAS/RNaseL pathway and its inhibition by viruses.

Abstract

RNaseL is a well-known effector of the type I interferon pathway. This review focuses on the recent developments of RNaseL activation and on the antagonism of the OAS-RNaseL pathway by viral proteins. Recent structural data show that two 2'-5' oligoadenylate molecules can bridge ankyrin domains of two RNaseL subunits bound in opposite orientations. The binding of nucleotides to the pseudokinase domain further strengthens the dimer and imparts an active conformation to the ribonuclease. The OAS/RNaseL pathway is active against many viruses and viruses evolved in several ways to escape this pathway. Influenza virus A acts upstream of this pathway by hiding double stranded RNA through its NS1 protein. In this way, it also inhibits the PKR and TLR-3 activation by double stranded RNA. Theiler's virus acts downstream of the OAS/RNaseL pathway, through the direct interaction between protein L* and RNaseL. By acting on the effector enzyme, Theiler's virus ensures a strong RNaseL inhibition, which seems to be particularly useful for the infection of macrophages. In conclusion, viruses have developed distinct strategies to escape RNaseL activity, that are likely dependent on their tropism. The fact that viral proteins have evolved to specifically antagonize RNaseL outlines the importance of this particular IFN effector in cells infected by those viruses.