Ribonuclease L

Last updated
RNASEL
Protein RNASEL PDB 1wdy.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases RNASEL , PRCA1, RNS4, ribonuclease L
External IDs OMIM: 180435; MGI: 1098272; HomoloGene: 8040; GeneCards: RNASEL; OMA:RNASEL - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6041

24014

Ensembl

ENSG00000135828

ENSMUSG00000066800

UniProt

Q05823

Q05921

RefSeq (mRNA)

NM_021133

NM_011882

RefSeq (protein)

NP_066956

NP_036012

Location (UCSC) Chr 1: 182.57 – 182.59 Mb Chr 1: 153.63 – 153.64 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Ribonuclease L or RNase L (for latent), known sometimes as ribonuclease 4 or 2'-5' oligoadenylate synthetase-dependent ribonuclease, is an interferon (IFN)-induced ribonuclease which, upon activation, destroys all RNA within the cell (both cellular and viral) as well as inhibiting mRNA export. [5] [6] RNase L is an enzyme that in humans is encoded by the RNASEL gene. [7]

Contents

This gene encodes a component of the interferon-regulated 2'-5'oligoadenylate (2'-5'A) system that functions in the antiviral and antiproliferative roles of interferons. RNase L is activated by dimerization, which occurs upon 2'-5'A binding, and results in cleavage of all RNA in the cell. This can lead to activation of MDA5, an RNA helicase involved in the production of interferons.

Synthesis and activation

RNase L activation pathway-IFN factors bind the receptor and lead transcription and modifications of OAS. Viral dsRNA binds OAS, so that 2'-5'A is produced leading to the dimerization of RNase L. Activated RNase L cleaves all RNA in the cell, which can activate MDA5 leading to interferon production. RNAse L Pathway new.png
RNase L activation pathway-IFN factors bind the receptor and lead transcription and modifications of OAS. Viral dsRNA binds OAS, so that 2'-5'A is produced leading to the dimerization of RNase L. Activated RNase L cleaves all RNA in the cell, which can activate MDA5 leading to interferon production.

RNase L is present in very minute quantities during the normal cell cycle. When interferon binds to cell receptors, it activates transcription of around 300 genes to bring about the antiviral state. Among the enzymes produced is RNase L, which is initially in an inactive form. A set of transcribed genes codes for 2'-5' Oligoadenylate Synthetase (OAS). [8] The transcribed RNA is then spliced and modified in the nucleus before reaching the cytoplasm and being translated into an inactive form of OAS. The location of OAS in the cell and the length of the 2'-5' oligoadenylate depends on the post-transcriptional and post-translational modifications of OAS. [8]

OAS is only activated under a viral infection, when a tight binding of the inactive form of the protein with a viral dsRNA, consisting of the retrovirus' ssRNA and its complementary strand, takes place. Once active, OAS converts ATP to pyrophosphate and 2'-5'-linked oligoadenylates (2-5A), which are 5' end phosphorylated. [9] 2-5 A molecules then bind to RNase L, promoting its activation by dimerization. In its activated form RNase L cleaves all RNA molecules in the cell leading to autophagy and apoptosis. Some of the resulting RNA fragments can also further induce the production of IFN-β as noted in the Significance section. [10]

This dimerization and activation of RNase L can be recognized using Fluorescence Resonance Energy Transfer (FRET), as oligoribonucleotides containing a quencher and a fluorophore on opposite sites are added to a solution with inactive RNase L. The FRET signal is then recorded as the quencher and the fluorophore are very close to each other. Upon the addition of 2-5A molecules, RNase L becomes active, cleaving the oligoribonucleotides and interfering in the FRET signal. [11]

In vitro, RNase L can be inhibited by curcumin. [12]

Significance

RNase L is part of the body's innate immune defense, namely the antiviral state of the cell. When a cell is in the antiviral state, it is highly resistant to viral attacks and is also ready to undergo apoptosis upon successful viral infection. Degradation of all RNA within the cell (which usually occurs with cessation of translation activity caused by protein kinase R) is the cell's last stand against a virus before it attempts apoptosis.

Interferon beta (IFN-β), a type I interferon responsible for antiviral activity, is induced by RNase L and melanoma differentiation-associated protein 5 (MDA5) in the infected cell. The relationship between RNase L and MDA5 in the production of IFNs has been confirmed with siRNA tests silencing the expression of either molecule and noting a marked decline in IFN production. [13] MDA5, an RNA helicase, is known to be activated by complex high molecular weight dsRNA transcribed from the viral genome. [13] [14] In a cell with RNase L, MDA5 activity may be further enhanced. [13] When active, RNase L cleaves and identifies viral RNA and feeds it into MDA5 activation sites, enhancing the production of IFN-β. The RNA fragments produced by RNase L have double stranded regions, as well as specific markers, that allow them to be identified by the RNase L and MDA5. [10] Some studies have suggested that high levels of RNase L may actually inhibit IFN-β production, but a clear linkage still exists between RNase L activity and IFN-β production. [10]

Furthermore, it has been shown that RNase L is involved in many diseases. In 2002, the "hereditary prostate cancer 1" locus (HPC1) was mapped to the RNASEL gene, indicating that mutations in this gene cause a predisposition to prostate cancer. [15] [16] [17] Impairments of the OAS/RNase L pathway in chronic fatigue syndrome (CFS) have been investigated. [18] [19]

Related Research Articles

<span class="mw-page-title-main">Interferon</span> Signaling proteins released by host cells in response to the presence of pathogens

Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.

<span class="mw-page-title-main">Dicer</span> Enzyme that cleaves double-stranded RNA (dsRNA) into short dsRNA fragments

Dicer, also known as endoribonuclease Dicer or helicase with RNase motif, is an enzyme that in humans is encoded by the DICER1 gene. Being part of the RNase III family, Dicer cleaves double-stranded RNA (dsRNA) and pre-microRNA (pre-miRNA) into short double-stranded RNA fragments called small interfering RNA and microRNA, respectively. These fragments are approximately 20–25 base pairs long with a two-base overhang on the 3′-end. Dicer facilitates the activation of the RNA-induced silencing complex (RISC), which is essential for RNA interference. RISC has a catalytic component Argonaute, which is an endonuclease capable of degrading messenger RNA (mRNA).

<i>Murine respirovirus</i> Sendai virus, virus of rodents

Murine respirovirus, formerly Sendai virus (SeV) and previously also known as murine parainfluenza virus type 1 or hemagglutinating virus of Japan (HVJ), is an enveloped, 150-200 nm–diameter, negative sense, single-stranded RNA virus of the family Paramyxoviridae. It typically infects rodents and it is not pathogenic for humans or domestic animals.

<span class="mw-page-title-main">Drosha</span> Ribonuclease III enzyme

Drosha is a Class 2 ribonuclease III enzyme that in humans is encoded by the DROSHA gene. It is the primary nuclease that executes the initiation step of miRNA processing in the nucleus. It works closely with DGCR8 and in correlation with Dicer. It has been found significant in clinical knowledge for cancer prognosis. and HIV-1 replication.

<span class="mw-page-title-main">Interferon type I</span> Cytokine

The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cytoband over approximately 400 kb including coding genes for IFNα, IFNω (IFNW1), IFNɛ (IFNE), IFNк (IFNK) and IFNβ (IFNB1), plus 11 IFN pseudogenes.

<span class="mw-page-title-main">Xenotropic murine leukemia virus–related virus</span> Species of virus

Xenotropic murine leukemia virus–related virus (XMRV) is a retrovirus which was first described in 2006 as an apparently novel human pathogen found in tissue samples from men with prostate cancer. Initial reports erroneously linked the virus to prostate cancer and later to chronic fatigue syndrome (CFS), leading to considerable interest in the scientific and patient communities, investigation of XMRV as a potential cause of multiple medical conditions, and public-health concerns about the safety of the donated blood supply.

<span class="mw-page-title-main">OAS1</span>

2'-5'-oligoadenylate synthetase 1 is an enzyme that in humans is encoded by the OAS1 gene.

<span class="mw-page-title-main">RIG-I</span> Mammalian protein found in humans

RIG-I is a cytosolic pattern recognition receptor (PRR) that can mediate induction of a type-I interferon (IFN1) response. RIG-I is an essential molecule in the innate immune system for recognizing cells that have been infected with a virus. These viruses can include West Nile virus, Japanese Encephalitis virus, influenza A, Sendai virus, flavivirus, and coronaviruses.

<span class="mw-page-title-main">IFNA2</span> Mammalian protein found in Homo sapiens

Interferon alpha-2 is a protein that in humans is encoded by the IFNA2 gene.

<span class="mw-page-title-main">Mitochondrial antiviral-signaling protein</span> Protein-coding gene in the species Homo sapiens

Mitochondrial antiviral-signaling protein (MAVS) is a protein that is essential for antiviral innate immunity. MAVS is located in the outer membrane of the mitochondria, peroxisomes, and mitochondrial-associated endoplasmic reticulum membrane (MAM). Upon viral infection, a group of cytosolic proteins will detect the presence of the virus and bind to MAVS, thereby activating MAVS. The activation of MAVS leads the virally infected cell to secrete cytokines. This induces an immune response which kills the host's virally infected cells, resulting in clearance of the virus.

<span class="mw-page-title-main">MDA5</span> Mammalian protein found in Homo sapiens

MDA5 is a RIG-I-like receptor dsRNA helicase enzyme that is encoded by the IFIH1 gene in humans. MDA5 is part of the RIG-I-like receptor (RLR) family, which also includes RIG-I and LGP2, and functions as a pattern recognition receptor capable of detecting viruses. It is generally believed that MDA5 recognizes double stranded RNA (dsRNA) over 2000nts in length, however it has been shown that whilst MDA5 can detect and bind to cytoplasmic dsRNA, it is also activated by a high molecular weight RNA complex composed of ssRNA and dsRNA. For many viruses, effective MDA5-mediated antiviral responses are dependent on functionally active LGP2. The signaling cascades in MDA5 is initiated via CARD domain. Some observations made in cancer cells show that MDA5 also interacts with cellular RNA is able to induce an autoinflammatory response.

<span class="mw-page-title-main">OAS2</span> Protein-coding gene in the species Homo sapiens

2'-5'-oligoadenylate synthetase 2 is an enzyme that in humans is encoded by the OAS2 gene.

<span class="mw-page-title-main">OASL</span> Protein-coding gene in the species Homo sapiens

59 kDa 2'-5'-oligoadenylate synthetase-like protein is an enzyme that in humans is encoded by the OASL gene.

<span class="mw-page-title-main">ISG20</span> Protein-coding gene in the species Homo sapiens

Interferon-stimulated gene 20 kDa protein is a protein that in humans is encoded by the ISG20 gene.

<span class="mw-page-title-main">OAS3</span> Protein-coding gene in the species Homo sapiens

2'-5'-oligoadenylate synthetase 3 is an enzyme that in humans is encoded by the OAS3 gene.

<span class="mw-page-title-main">Antiviral protein</span>

Antiviral proteins are proteins that are induced by human or animal cells to interfere with viral replication. These proteins are isolated to inhibit the virus from replicating in a host's cells and stop it from spreading to other cells. The Pokeweed antiviral protein and the Zinc-Finger antiviral protein are two major antiviral proteins that have undergone several tests for viruses, including HIV and influenza.

RIG-I-like receptors are a type of intracellular pattern recognition receptor involved in the recognition of viruses by the innate immune system. RIG-I is the best characterized receptor within the RIG-I like receptor (RLR) family. Together with MDA5 and LGP2, this family of cytoplasmic pattern recognition receptors (PRRs) are sentinels for intracellular viral RNA that is a product of viral infection. The RLR receptors provide frontline defence against viral infections in most tissues.

<span class="mw-page-title-main">2'-5'-oligoadenylate synthase</span>

In molecular biology, 2'-5'-oligoadenylate synthetase is an enzyme that reacts to interferon signal. It is an antiviral enzyme that counteracts viral attack by degrading RNAs, both viral and host. The enzyme uses ATP in 2'-specific nucleotidyl transfer reactions to synthesize 2'-5'-oligoadenylates, which activate latent ribonuclease (RNase-L), resulting in degradation of viral RNA and inhibition of virus replication.

An interferon-stimulated gene (ISG) is a gene that can be expressed in response to stimulation by interferon. Interferons bind to receptors on the surface of a cell, initiating protein signaling pathways within the cell. This interaction leads to the expression of a subset of genes involved in the innate immune system response. ISGs are commonly expressed in response to viral infection, but also during bacterial infection and in the presence of parasites. It's currently estimated that 10% of the human genome is regulated by interferons (IFNs). Interferon stimulated genes can act as an initial response to pathogen invasion, slowing down viral replication and increasing expression of immune signaling complexes. There are three known types of interferon. With approximately 450 genes highly expressed in response to interferon type I. Type I interferon consists of INF-α, INF-β, INF-ω and is expressed in response to viral infection. ISGs induced by type I interferon are associated with viral replication suppression and increase expression of immune signaling proteins. Type II interferon consists only of INF-γ and is associated with controlling intracellular pathogens and tumor suppressor genes. Type III interferon consists of INF-λ and is associated with viral immune response and is key in anti-fungal neutrophil response.

<span class="mw-page-title-main">Viral strategies for immune response evasion</span>

The mammalian immune system has evolved complex methods for addressing and adapting to foreign antigens. At the same time, viruses have co-evolved evasion machinery to address the many ways that host organisms attempt to eradicate them. DNA and RNA viruses use complex methods to evade immune cell detection through disruption of the Interferon Signaling Pathway, remodeling of cellular architecture, targeted gene silencing, and recognition protein cleavage.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000135828 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000066800 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Brennan-Laun, Sarah E.; Ezelle, Heather J.; Li, Xiao-Ling; Hassel, Bret A. (April 2014). "RNase-L Control of Cellular mRNAs: Roles in Biologic Functions and Mechanisms of Substrate Targeting". Journal of Interferon & Cytokine Research. 34 (4): 275–288. doi:10.1089/jir.2013.0147. ISSN   1079-9907. PMC   3976596 . PMID   24697205.
  6. ↑ Burke, James M.; Gilchrist, Alison R.; Sawyer, Sara L.; Parker, Roy (2021-06-04). "RNase L limits host and viral protein synthesis via inhibition of mRNA export". Science Advances. 7 (23). doi:10.1126/sciadv.abh2479. ISSN   2375-2548. PMC   8177694 . PMID   34088676.
  7. ↑ Squire J, Zhou A, Hassel BA, Nie H, Silverman RH (January 1994). "Localization of the interferon-induced, 2-5A-dependent RNase gene (RNS4) to human chromosome 1q25". Genomics. 19 (1): 174–5. doi:10.1006/geno.1994.1033. PMID   7514564.
  8. 1 2 Sarkar SN, Pandey M, Sen GC (2005). "Assays for the Interferon-Induced Enzyme 2′,5′ Oligoadenylate Synthetases". Interferon Methods and Protocols. Methods in Molecular Medicine. Vol. 116. Human Press Inc. pp. 81–101. doi:10.1385/1-59259-939-7:081. ISBN   978-1-58829-418-0. PMID   16000856.
  9. ↑ Liang SL, Quirk D, Zhou A (September 2006). "RNase L: its biological roles and regulation". IUBMB Life. 58 (9): 508–14. doi: 10.1080/15216540600838232 . PMID   17002978.
  10. 1 2 3 Banerjee S, Chakrabarti A, Jha BK, Weiss SR, Silverman RH (February 2014). "Cell-type-specific effects of RNase L on viral induction of beta interferon". mBio. 5 (2): e00856-14. doi:10.1128/mBio.00856-14. PMC   3940032 . PMID   24570368.
  11. ↑ Thakur CS, Xu Z, Wang Z, Novince Z, Silverman RH (2005). "A Convenient and Sensitive Fluorescence Resonance Energy Transfer Assay for RNase L and 2′,5′ Oligoadenylates". Interferon Methods and Protocols. Methods in Molecular Medicine. Vol. 116. Human Press Inc. pp. 103–13. doi:10.1385/1-59259-939-7:103. ISBN   978-1-58829-418-0. PMID   16000857.
  12. ↑ Gupta A, Rath PC (2014). "Curcumin, a natural antioxidant, acts as a noncompetitive inhibitor of human RNase L in presence of its cofactor 2-5A in vitro". BioMed Research International. 2014: 817024. doi: 10.1155/2014/817024 . PMC   4165196 . PMID   25254215.
  13. 1 2 3 Luthra P, Sun D, Silverman RH, He B (February 2011). "Activation of IFN-β expression by a viral mRNA through RNase L and MDA5". Proceedings of the National Academy of Sciences of the United States of America. 108 (5): 2118–23. Bibcode:2011PNAS..108.2118L. doi: 10.1073/pnas.1012409108 . PMC   3033319 . PMID   21245317.
  14. ↑ Pichlmair A, Schulz O, Tan CP, Rehwinkel J, Kato H, Takeuchi O, et al. (October 2009). "Activation of MDA5 requires higher-order RNA structures generated during virus infection". Journal of Virology. 83 (20): 10761–9. doi:10.1128/JVI.00770-09. PMC   2753146 . PMID   19656871.
  15. ↑ Smith JR, Freije D, Carpten J, Gronberg H, Xu J, Isaacs S, et al. (Nov 1996). "Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search". Science. 274 (5291): 1371–4. Bibcode:1996Sci...274.1371S. doi:10.1126/science.274.5291.1371. PMID   8910276. S2CID   42684655.
  16. ↑ "Entrez Gene: RNASEL ribonuclease L (2',5'-oligoisoadenylate synthetase-dependent)".
  17. ↑ Carpten J, Nupponen N, Isaacs S, Sood R, Robbins C, Xu J, et al. (February 2002). "Germline mutations in the ribonuclease L gene in families showing linkage with HPC1". Nature Genetics. 30 (2): 181–4. doi:10.1038/ng823. PMID   11799394. S2CID   2922306.
  18. ↑ Nijs J, De Meirleir K (Nov–Dec 2005). "Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome". In Vivo. 19 (6): 1013–21. PMID   16277015.
  19. ↑ Suhadolnik RJ, Peterson DL, O'Brien K, Cheney PR, Herst CV, Reichenbach NL, et al. (July 1997). "Biochemical evidence for a novel low molecular weight 2-5A-dependent RNase L in chronic fatigue syndrome". Journal of Interferon & Cytokine Research. 17 (7): 377–85. doi:10.1089/jir.1997.17.377. PMID   9243369.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.