Disease relevance of Rnasel

• Surprisingly, cultured embryonic fibroblasts lacking RNase L, PKR, or both proteins were still able to mount a substantial residual antiviral response against encephalomyocarditis virus or vesicular stomatitis virus after IFN-alpha treatments [1].
• Critical role for the oligoadenylate synthetase/RNase L pathway in response to IFN-beta during acute ocular herpes simplex virus type 1 infection [2].
• RNase L and double-stranded RNA-dependent protein kinase exert complementary roles in islet cell defense during coxsackievirus infection [3].
• RNase L plays a role in the antiviral response to West Nile virus [4].
• The data indicate that WNV genomic RNA is susceptible to RNase L cleavage and that RNase L plays a role in the cellular antiviral response to flaviviruses [4].

High impact information on Rnasel

• 2-5A-dependent RNAase, an interferon-induced enzyme that is activated by 5'-phosphorylated, 2',5'-linked oligoadenylates (2-5A), is implicated in both the molecular mechanisms of interferon action and the fundamental control of RNA stability in mammalian cells [5].
• Interferon action and apoptosis are defective in mice devoid of 2',5'-oligoadenylate-dependent RNase L [6].
• In addition, remarkably enlarged thymuses in the RNase L-/- mice resulted from a suppression of apoptosis [6].
• There was a 2-fold decrease in apoptosis in vivo in the thymuses and spleens of RNase L-/- mice [6].
• It inhibits activation of the 2-5A-dependent RNase by 2-5A in intact mouse L929 cells and cell-free systems [7].

Biological context of Rnasel

• The results suggest that RNase L activation is not a major component of the Oas1b-mediated flavivirus resistance phenotype [4].
• Furthermore, ectopic expression of RNase L from a plasmid vector prevented the IFN induction of PKR [8].
• However, the efficacy of Ad:IFN-beta was lost in the corneas of RNase L(-/-) mice and significantly diminished in both the cornea and trigeminal ganglion as measured by viral gene expression in RNA-dependent protein kinase deficient mice [9].
• Dichotomy between survival and lytic gene expression in RNase L- and PKR-deficient mice transduced with an adenoviral vector expressing murine IFN-beta following ocular HSV-1 infection [9].
• The absence of PKR but not RNase L significantly attenuated the antiviral efficacy of the transgene [10].

Anatomical context of Rnasel

• Notably, a deficiency in both PKR and RNase L resulted in a decreased ability of type I IFN to inhibit WNV in primary macrophages and cortical neurons [11].
• Sindbis virus translation is inhibited by a PKR/RNase L-independent effector induced by alpha/beta interferon priming of dendritic cells [12].
• The murine double-stranded RNA-dependent protein kinase PKR and the murine 2',5'-oligoadenylate synthetase-dependent RNase L are required for IFN-beta-mediated resistance against herpes simplex virus type 1 in primary trigeminal ganglion culture [13].
• Although the permissivity of cells in lymph nodes draining the inoculation site was increased in the absence of PKR/RNase L, systemic dissemination of the virus infection was restricted by an alternative IFN-alpha/beta receptor-dependent mechanism [14].
• Therefore, RNase L is directly involved in myoblast differentiation, probably through its role in regulating MyoD stability [15].

Associations of Rnasel with chemical compounds

• Induction of RNase-L expression in mouse 3T3 fibroblasts further decreased the monensin-induced reduction in mt-mRNA half-life to 1.5h [16].
• In monensin (250 nM)-treated RNase-L(+/+) cells the average half-life of mt-mRNA, determined after termination of transcription with actinomycin D, was found to be 3h, whereas in monensin-treated RNase-L(-/-) cells the half-life of mt-mRNA was >6h [16].
• In agreement with these data, MyoD mRNA levels were also decreased in C2 cells transfected with an inducible RNase L construct [15].
• Upon interferon activation by dsRNA, 2',5'-oligoadenylate synthetase 1 (OAS1A) is induced; it binds dsRNA and converts ATP into 2',5'-linked oligomers of adenosine (called 2-5A), which activate RNase L that in turn degrades viral and cellular RNAs [17].
• Both binding and activation of mouse liver 2-5A dependent ribonuclease (RNase L) by the various 8-methyladenosine-substituted 2-5A analogues were examined [18].

Regulatory relationships of Rnasel

• Finally, RNase L(-/-) transgenic mice were undistinguishable from controls under basal conditions and after poly(I-C) or IFN-gamma administration, suggesting that RNase L does not modulate HBV replication in this model [19].
• RNase L is a latent endoribonuclease which is activated by 2-5A and inhibited by a specific protein known as RLI (RNase L inhibitor) [15].

Other interactions of Rnasel

• Here we report that in mouse embryo fibroblasts that are devoid of the interferon-regulated RNase, RNase-L, the monensin-induced decrease in the half-life of mt-mRNA was reduced [16].
• Furthermore, our results indicate the existence of an interferon-mediated antipoxvirus pathway that operates independently of PKR, Mx1, or the 2-5A/RNase L system [20].
• Activation of NF-kappaB by double-stranded RNA (dsRNA) in the absence of protein kinase R and RNase L demonstrates the existence of two separate dsRNA-triggered antiviral programs [21].
• These responses are essentially intact in the absence of PKR and/or RNase L (K. D. Ryman, L. J. White, R. E. Johnston, and W. B. Klimstra, Viral Immunol. 15:53-76, 2002) [12].
• Here, we investigated the individual and combined contributions of the two best characterized INF-alpha/beta-mediated antiviral pathways to the control of Sindbis virus replication: (1) the coupled 2-5A synthetase/RNase L pathway and (2) the double-stranded RNA-dependent protein kinase (PKR) pathway [14].

Analytical, diagnostic and therapeutic context of Rnasel

• Although mice lacking RNase L showed a higher CNS viral burden and an increased mortality, they were less susceptible than the PKR(-/-) x RL(-/-) mice; thus, we also infer an antiviral role for PKR in the control of WNV infection [11].
• In Western blot, only the 80-kDa form of RNase L is recognized by these antibodies [22].
• These purified antibodies were used to localize RNase L in the cytoplasm of intact mouse NIH 3T3 cells by immunofluorescence [22].
• Phase-contrast microscopy, EM, flow cytometry, and rRNA analyses demonstrated that contrary to MVA, NYVAC infection induces potent apoptosis, a phenomenon dependent on activation of caspases and RNase L [23].
• Interestingly, Sin85B vaccination did not protect RNase L-/- (a key enzyme in the innate antiviral response) mice while significant protection was detected in RNase L-/- mice immunized with either BCG or a conventional DNA plasmid expressing antigen 85B [24].

References