The interplay between RNase L and the host cell or viruses: A review

Ribonuclease L (RNase L), which is the effector enzyme of the oligoadenylate synthesis (OAS) /RNase L pathway, exerts its antiviral immune response by cleaving both viral and cellular single-stranded RNA (ssRNA). Beyond its role in innate immunity, RNase L is critically involved in various cellular biological processes and has been linked to disease processes. The interplay between RNase L and the host cell is essential for maintaining intracellular homeostasis and displays the antiviral function. The activation of RNase L is tightly regulated by cellular components such as RNA, 2'-phosphodiesterase (2'-PDE), and RNase L inhibitor (RLI). Conversely, nonactivated or activated RNase L regulates multiple host cellular biological processes, including RNA decay, autophagy and apoptosis crosstalk, and the formation of biological condensates. During viral replication, double-stranded RNA (dsRNA) activates OAS and synthesizes 2',5' oligoadenylate (2-5 A) from ATP. RNase L is activated by binding with 2-5 A to mediate an antiviral immune response by cleavage of viral RNA, thereby suppressing viral replication and infection. Viruses have evolved multiple mechanisms to antagonize the antiviral activity of RNase L, including suppressing OAS activity, upregulating viral 2',5'-PDE expression, and inhibiting the RNA cleavage function of RNase L. In light of recent biochemical and functional findings on RNase L, this review provides a comprehensive overview of its direct or indirect function in host antiviral immune response and diverse strategies that viruses employ to antagonize RNase L activity.