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Ribonuclease L

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(Redirected from RNase L)
RNASEL
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesRNASEL, PRCA1, RNS4, ribonuclease L
External IDsOMIM: 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 MbChr 1: 153.63 – 153.64 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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]

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

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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

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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]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000135828 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b 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. ^ a b c 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. ^ a b c 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

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