New advances in our understanding of the “unique” RNase L in host pathogen interaction and immune signaling

Abstract

Ever since the discovery of the existence of an interferon (IFN)-regulated ribonuclease, significant advances have been made in understanding the mechanism and associated regulatory effects of its action. What had been studied initially as a "unique" endoribonuclease is currently known as ribonuclease L (RNase L where "L" stands for latent). Some of the key developments include discovery of the RNase L signaling pathway, its structural characterization, and its molecular cloning. RNase L has been implicated in antiviral and antibacterial defense, as well as in hereditary prostate cancer. RNase L is activated by 2'-5' linked oligoadenylates (2-5A), which are synthesized by the oligoadenylate synthetases (OASs), a family of IFN-regulated pathogen recognition receptors that sense double-stranded RNAs. Activated RNase L cleaves single stranded RNAs, including viral RNAs and cellular RNAs. The catalytic activity of RNase L has been found to lead into the activation of several cellular signaling pathways, including those involved in autophagy, apoptosis, IFN-β production, NLRP3 inflammasome activation leading to IL-1β secretion, inhibition of cell migration, and cell adhesion. In this review, we will highlight the newest advances in our understanding of the catalytic role of RNase L in the context of different cellular pathways and extend the scope of these findings to discussion of potential therapeutic targets for antimicrobial drug development.

TMEM41B is a pan-flavivirus host factor

“…Upon detection of viral PAMPs, cells secrete IFN to protect neighboring cells from infection then subsequently initiate apoptosis ( Drappier and Michiels, 2015 ; Gusho et al, 2020 ; Schwartz and Conn, 2019 ). To assay if the cytotoxicity we observed in TMEM41B KO cells after inoculation with high viral loads was in fact apoptosis, we inoculated wildtype and TMEM41B KO cells with a high YFV 17D inoculum (MOI = 4 PFU/cell) and quantified the number of apoptotic cells at 24 h post inoculation.…”

All About the RNA: Interferon-Stimulated Genes That Interfere With Viral RNA Processes

“…ZAP is also able to repress translation of a luciferase reporter containing the minimal ZAP responsive fragment in the SINV genome without promoting degradation of the reporter ( 142 ). More recently, the E3 ligase tripartite motif-containing protein 25 (TRIM25) was uncovered as a novel ZAP co-factor in the context of alphavirus infection ( 47 , 143 ). TRIM25 is absolutely required for inhibition of viral translation by ZAP, as ZAP is unable to inhibit translation of a replication-deficient reporter virus in TRIM25-deficient cells ( 47 ).…”

“…More recently, the E3 ligase tripartite motif-containing protein 25 (TRIM25) was uncovered as a novel ZAP co-factor in the context of alphavirus infection ( 47 , 143 ). TRIM25 is absolutely required for inhibition of viral translation by ZAP, as ZAP is unable to inhibit translation of a replication-deficient reporter virus in TRIM25-deficient cells ( 47 ). Not only is TRIM25 putatively required for ZAP recognition of its RNA substrates, as TRIM25 knockdown decreases ZAP association with luciferase reporter RNA, but also TRIM25 ubiquitin ligase activity is essential for ZAP antiviral activity ( 47 , 143 ).…”

Viral pathogen-induced mechanisms to antagonize mammalian interferon (IFN) signaling pathway

“…The oligoadenylate synthetase (OAS)-latent RNase (RNase L) pathway is another IFN-inducible pathway that provides the cell with an effector mechanism upon recognition of viral dsRNA (reviewed in [ 44 ]). When the OAS senses dsRNA activates the production of 2′,5′-oligoadenylates that act as a second messenger on the inactive monomeric RNaseL [ 45 ].…”