OAS/RNase L systgeemi. Primäärinen virus vaste dsRNA viruksen havaitsemisessa

 Sitaatti: 
"Also the 2´-5´ oligoadenylate synthetase (OAS)  family members are triggered by viral dsRNA (2011). In the dsRNA-bound state they synthetize short chains of 2´-5´ oligoadenylates that activate the latent RNase L. RNase L then cleaves virus and host ssRNAs, predominantly at single stranded UA and UU dinucleotides (Wreschner 1981). Interestingly, the small 3´-monophosphorylated cleavage products of RNase L are recognized by the PRRs RIG-1 and MDA5, thus amplifying the IFN response in an infection-dependent manner(Malathi , 2007). polymorphism of the OAS-1 gene might affect susceptibility  to SARS-CoV (Hamano, 2005), but to our knowledge, there is no direct data on antiviral effects of the OAS/RNase L system on human coronaviruses.  For the mouse coronavirus MHV-A59, however, it was shown that mutants deficient in the ns2 gene are highly sensitive against RNaSE l 8zHAO 2012). "
Kindler E e al.  INTERACTION OF SARS AND MERS CORONAVIRUSES WITH THE ANTIVIRAL INTERFERON RESPONSE. 
http://dx.doi.org/10.1016/bs.aivir.2016.08.006 http://dx.doi.org/10.1016/bs.aivir.2016.08.006

• Etsin lisätietoa OAS/RNase L  tiestä yleensä.

https://pubmed.ncbi.nlm.nih.gov/?term=OAS%2FRNase+L+system

• Inhibition of the OAS/RNase L pathway by viruses.

Drappier M, Michiels T. Curr Opin Virol. 2015 Dec;15:19-26. doi: 10.1016/j.coviro.2015.07.002. Epub 2015 Jul 29. PMID: 26231767 Free PMC article. Review.

The OAS/RNase L system was one of the first characterized interferon effector pathways. It relies on the synthesis, by oligoadenylate synthetases (OAS), of short oligonucleotides that act as second messengers to activate the latent cellular RNase L. Viruses have developed diverse strategies to escape its antiviral effects. This underscores the importance of the OAS/RNase L pathway in antiviral defenses. Viral proteins such as the NS1 protein of Influenza virus A act upstream of the pathway while other viral proteins such as Theiler's virus L* protein act downstream. The diversity of escape strategies used by viruses likely stems from their relative susceptibility to OAS/RNase L and other antiviral pathways, which may depend on their host and cellular tropism.

 

• Activation of RNase L in Egyptian Rousette Bat-Derived RoNi/7 Cells Is Dependent Primarily on OAS3 and Independent of MAVS Signaling.

Li Y, Dong B, Wei Z, Silverman RH, Weiss SR. mBio. 2019 Nov 12;10(6):e02414-19. doi: 10.1128/mBio.02414-19. PMID: 31719180 Free PMC article.

Bats are reservoirs for many RNA viruses that are highly pathogenic in humans yet relatively apathogenic in the natural host. It has been suggested that differences in innate immunity are responsible. The antiviral OAS-RNase L pathway is well characterized in humans, but there is little known about its activation and antiviral activity in bats. During infection, OASs, upon sensing double-stranded RNA (dsRNA), produce 2'-5' oligoadenylates (2-5A), leading to activation of RNase L which degrades viral and host RNA, limiting viral replication. Humans encode three active OASs (OAS1 to -3). Analysis of the Egyptian Rousette bat genome combined with mRNA sequencing from bat RoNi/7 cells revealed three homologous OAS proteins. Interferon alpha treatment or viral infection induced all three OAS mRNAs, but RNase L mRNA is constitutively expressed.

 Sindbis virus (SINV) or vaccinia virus (VACVΔE3L) infection of wild-type (WT) or OAS1-KO (knockout), OAS2-KO, or MAVS-KO RoNi/7 cells, but not RNase L-KO or OAS3-KO cells, induces robust RNase L activation. SINV replication is 100- to 200-fold higher in the absence of RNase L or OAS3 than in WT cells. However, MAVS-KO had no detectable effect on RNA degradation or replication. Thus, in RoNi/7 bat cells, as in human cells, activation of RNase L during infection and its antiviral activity are dependent primarily on OAS3 while MAVS signaling is not required for the activation of RNase L and restriction of infection. 

Our findings indicate that OAS proteins serve as pattern recognition receptors (PRRs) to recognize viral dsRNA and that this pathway is a primary response to virus rather than a secondary effect of interferon signaling. 

IMPORTANCE Many RNA viruses that are highly pathogenic in humans are relatively apathogenic in their bat reservoirs, making it important to compare innate immune responses in bats to those well characterized in humans. One such antiviral response is the OAS-RNase L pathway. OASs, upon sensing dsRNA, produce 2-5A, leading to activation of RNase L which degrades viral and host RNA, limiting viral replication. 

Analysis of Egyptian Rousette bat sequences revealed three OAS genes expressing OAS1, OAS2, and OAS3 proteins. Interferon treatment or viral infection induces all three bat OAS mRNAs. In these bat cells as in human cells, RNase L activation and its antiviral activity are dependent primarily on OAS3 while MAVS signaling is not required.

 Importantly, our findings indicate the OAS-RNase L system is a primary response to virus rather than a secondary effect of interferon signaling and therefore can be activated early in infection or while interferon signaling is antagonized.

 

• Molecular Mechanisms for the Adaptive Switching Between the OAS/RNase L and OASL/RIG-I Pathways in Birds and Mammals.

Rong E, Wang X, Chen H, Yang C, Hu J, Liu W, Wang Z, Chen X, Zheng H, Pu J, Sun H, Smith J, Burt DW, Liu J, Li N, Huang Y. Front Immunol. 2018 Jun 20;9:1398. doi: 10.3389/fimmu.2018.01398. eCollection 2018. PMID: 29973937 Free PMC article.

Abstract

Host cells develop
(*) the OAS/RNase L [2'-5'-oligoadenylate synthetase (OAS)/ribonuclease L] system to degrade cellular and viral RNA, and/or
(**) the OASL/RIG-I (2'-5'-OAS like/retinoic acid inducible protein I) system to enhance RIG-I-mediated IFN induction,
 thus providing the first line of defense against viral infection.
( *)The 2'-5'-OAS-like (OASL) protein may activate the OAS/RNase L system using its typical OAS-like domain (OLD) 
or(**)mimic the K63-linked pUb to enhance antiviral activity of the OASL/RIG-I system using its two tandem ubiquitin-like domains (UBLs).
We first describe that divergent avian (duck and ostrich) OASL inhibit the replication of a broad range of RNA viruses by activating and magnifying the OAS/RNase L pathway(***) in a UBL-dependent manner.
This is in sharp contrast to mammalian enzymatic OASL, which activates and magnifies (*) the OAS/RNase L pathway   in a UBL-independent manner, similar to 2'-5'-oligoadenylate synthetase 1 (OAS1).
 We further show that both avian and mammalian OASL can reversibly exchange to activate and magnify the OAS/RNase L and OASL/RIG-I system by introducing only three key residues, suggesting that ancient OASL possess 2-5A [p_x5'A(2'p5'A)_n; x = 1-3; n ≥ 2] activity and has functionally switched to the OASL/RIG-I pathway recently. Our findings indicate the molecular mechanisms involved in the switching of avian and mammalian OASL molecules to activate and enhance the OAS/RNase L and OASL/RIG-I pathways in response to infection by RNA viruses.

 

• RNA regulation of the antiviral protein 2'-5'-oligoadenylate synthetase.

Schwartz SL, Conn GL. Wiley Interdiscip Rev RNA. 2019 Jul;10(4):e1534. doi: 10.1002/wrna.1534. Epub 2019 Apr 15. PMID: 30989826 Review.

The innate immune system is a broad collection of critical intra- and extra-cellular processes that limit the infectivity of diverse pathogens. The 2'-5'-oligoadenylate synthetase (OAS) family of enzymes are important sensors of cytosolic double-stranded RNA (dsRNA) that play a critical role in limiting viral infection by activating the latent ribonuclease (RNase L) to halt viral replication and establish an antiviral state. 

Attesting to the importance of the OAS/RNase L pathway, diverse viruses have developed numerous distinct strategies to evade the effects of OAS activation. How OAS proteins are regulated by viral or cellular RNAs is not fully understood but several recent studies have provided important new insights into the molecular mechanisms of OAS activation by dsRNA. Other studies have revealed unanticipated features of RNA sequence and structure that strongly enhance activation of at least one OAS family member. While these discoveries represent important advances, they also underscore the fact that much remains to be learned about RNA-mediated regulation of the OAS/RNase L pathway.  

 In particular, defining the full complement of RNA molecular signatures that activate OAS is essential to our understanding of how these proteins maximize their protective role against pathogens while still accurately discriminating host molecules to avoid inadvertent activation by cellular RNAs. A more complete knowledge of OAS regulation may also serve as a foundation for the development of novel antiviral therapeutic strategies and lead the way to a deeper understanding of currently unappreciated cellular functions of the OAS/RNase L pathway in the absence of infection. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications Translation > Translation Regulation. 

 

• ADAR1: "Editor-in-Chief" of Cytoplasmic Innate Immunity.

Lamers MM, van den Hoogen BG, Haagmans BL. Front Immunol. 2019 Jul 25;10:1763. doi: 10.3389/fimmu.2019.01763. eCollection 2019. PMID: 31404141 Free PMC article. Review.

Specialized receptors that recognize molecular patterns such as double stranded RNA duplexes-indicative of viral replication-are potent triggers of the innate immune system.

 Although their activation is beneficial during viral infection, RNA transcribed from endogenous mobile genetic elements may also act as ligands potentially causing autoimmunity. Recent advances indicate that the adenosine deaminase ADAR1 through RNA editing is involved in dampening the canonical antiviral RIG-I-like receptor-, PKR-, and OAS-RNAse L pathways to prevent autoimmunity. However, this inhibitory effect must be overcome during viral infections. In this review we discuss ADAR1's critical role in balancing immune activation and self-tolerance.

• RNase L activates the NLRP3 inflammasome during viral infections.

Chakrabarti A, Banerjee S, Franchi L, Loo YM, Gale M Jr, Núñez G, Silverman RH. Cell Host Microbe. 2015 Apr 8;17(4):466-77. doi: 10.1016/j.chom.2015.02.010. Epub 2015 Mar 26. PMID: 25816776 Free PMC article.

The NLRP3 inflammasome assembles in response to danger signals, triggering self-cleavage of procaspase-1 and production of the proinflammatory cytokine IL-1β. 

 Although virus infection activates the NLRP3 inflammasome, the underlying events remain incompletely understood. We report that virus activation of the NLRP3 inflammasome involves the 2',5'-oligoadenylate (2-5A) synthetase(OAS)/RNase L system, a component of the interferon-induced antiviral response that senses double-stranded RNA and activates endoribonuclease RNase L to cleave viral and cellular RNAs. The absence of RNase L reduces IL-1β production in influenza A virus-infected mice. RNA cleavage products generated by RNase L enhance IL-1β production but require the presence of 2',3'-cyclic phosphorylated termini characteristic of RNase L activity. Additionally, these cleavage products stimulate NLRP3 complex formation with the DExD/H-box helicase, DHX33, and mitochondrial adaptor protein, MAVS, which are each required for effective NLRP3 inflammasome activation. Thus, RNA cleavage events catalyzed by RNase L are required for optimal inflammasome activation during viral infections.