Internal Ribosomal Entry Site-mediated Translational Activity of Nitric Oxide Synthase 2

Overview

Journal Anim Cells Syst (Seoul)

Specialty Biology

Date 2024 Feb 28

PMID 38414531

Authors

Kyung-Ha Lee

Affiliations

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Abstract

The internal ribosome entry site (IRES) is a unique structure found in the 5' untranslated region (5'-UTR) of specific messenger RNAs (mRNAs) that allows ribosomes to bind and initiate translation without the need for a cap structure. In this study, we investigated the presence and functional properties of the IRES activity of nitric oxide synthase 2 (NOS2) mRNA, which encodes an enzyme that produces nitric oxide in response to various stimuli such as inflammation. Nitric oxide is a signaling molecule that plays a crucial role in various physiological processes, including immune responses and neuronal signaling. Our results showed the existence of IRES activity in the 5'-UTR of Nos2 mRNA in various cell types. IRES-mediated translation of NOS2 mRNA was higher in neuronal cells and its activity increased in response to lipopolysaccharide (LPS). Despite inhibition of cap-dependent translation, nitrite production was partially maintained. These results demonstrate the presence of IRES activity in the 5'-UTR of NOS2 mRNA and suggest that IRES-mediated translation plays a key role in controlling nitric oxide production in response to LPS, an inflammatory stimulus.

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References

Lee K, Kim S, Kim D, Kim S, Kim K . Internal ribosomal entry site-mediated translation is important for rhythmic PERIOD1 expression. PLoS One. 2012; 7(5):e37936. PMC: 3360671. DOI: 10.1371/journal.pone.0037936. View

Esplugues J . NO as a signalling molecule in the nervous system. Br J Pharmacol. 2002; 135(5):1079-95. PMC: 1573233. DOI: 10.1038/sj.bjp.0704569. View

Wang Z, Weaver M, Magnuson N . Cryptic promoter activity in the DNA sequence corresponding to the pim-1 5'-UTR. Nucleic Acids Res. 2005; 33(7):2248-58. PMC: 1083428. DOI: 10.1093/nar/gki523. View

Lee K, Kim S, Kim H, Kim W, Lee H, Jung Y . AUF1 contributes to Cryptochrome1 mRNA degradation and rhythmic translation. Nucleic Acids Res. 2014; 42(6):3590-606. PMC: 3973335. DOI: 10.1093/nar/gkt1379. View

Fitzgerald K, Semler B . Bridging IRES elements in mRNAs to the eukaryotic translation apparatus. Biochim Biophys Acta. 2009; 1789(9-10):518-28. PMC: 2783899. DOI: 10.1016/j.bbagrm.2009.07.004. View

Grover R, Sharathchandra A, Ponnuswamy A, Khan D, Das S . Effect of mutations on the p53 IRES RNA structure: implications for de-regulation of the synthesis of p53 isoforms. RNA Biol. 2011; 8(1):132-42. DOI: 10.4161/rna.8.1.14260. View

Jang S, Krausslich H, Nicklin M, Duke G, Palmenberg A, Wimmer E . A segment of the 5' nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. J Virol. 1988; 62(8):2636-43. PMC: 253694. DOI: 10.1128/JVI.62.8.2636-2643.1988. View

Yang Y, Wang Z . IRES-mediated cap-independent translation, a path leading to hidden proteome. J Mol Cell Biol. 2019; 11(10):911-919. PMC: 6884710. DOI: 10.1093/jmcb/mjz091. View

Sanchez de Groot N, Armaos A, Grana-Montes R, Alriquet M, Calloni G, Vabulas R . RNA structure drives interaction with proteins. Nat Commun. 2019; 10(1):3246. PMC: 6642211. DOI: 10.1038/s41467-019-10923-5. View

10.

Fan H, Yang J, Zhang K, Xing J, Guo B, Mao H . IRES-mediated Wnt2 translation in apoptotic neurons triggers astrocyte dedifferentiation. NPJ Regen Med. 2022; 7(1):42. PMC: 9440034. DOI: 10.1038/s41536-022-00248-1. View

11.

Lechner M, Lirk P, Rieder J . Inducible nitric oxide synthase (iNOS) in tumor biology: the two sides of the same coin. Semin Cancer Biol. 2005; 15(4):277-89. DOI: 10.1016/j.semcancer.2005.04.004. View

12.

Pelletier J, Sonenberg N . Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature. 1988; 334(6180):320-5. DOI: 10.1038/334320a0. View

13.

Ji B, Harris B, Liu Y, Deng Y, Gradilone S, Cleary M . Targeting IRES-Mediated p53 Synthesis for Cancer Diagnosis and Therapeutics. Int J Mol Sci. 2017; 18(1). PMC: 5297727. DOI: 10.3390/ijms18010093. View

14.

Wang X, Gray Z, Willette-Brown J, Zhu F, Shi G, Jiang Q . Macrophage inducible nitric oxide synthase circulates inflammation and promotes lung carcinogenesis. Cell Death Discov. 2018; 4:46. PMC: 5967330. DOI: 10.1038/s41420-018-0046-5. View

15.

Kim W, Shin J, Lee K, Kim K . PTBP1 Positively Regulates the Translation of Circadian Clock Gene, . Int J Mol Sci. 2020; 21(18). PMC: 7555454. DOI: 10.3390/ijms21186921. View

16.

Bechade C, Colasse S, Diana M, Rouault M, Bessis A . NOS2 expression is restricted to neurons in the healthy brain but is triggered in microglia upon inflammation. Glia. 2014; 62(6):956-63. DOI: 10.1002/glia.22652. View

17.

Han B, Zhang J . Regulation of gene expression by internal ribosome entry sites or cryptic promoters: the eIF4G story. Mol Cell Biol. 2002; 22(21):7372-84. PMC: 135655. DOI: 10.1128/MCB.22.21.7372-7384.2002. View

18.

Tuteja N, Chandra M, Tuteja R, Misra M . Nitric Oxide as a Unique Bioactive Signaling Messenger in Physiology and Pathophysiology. J Biomed Biotechnol. 2004; 2004(4):227-237. PMC: 555773. DOI: 10.1155/S1110724304402034. View

19.

Mattila J, Thomas A . Nitric oxide synthase: non-canonical expression patterns. Front Immunol. 2014; 5:478. PMC: 4191211. DOI: 10.3389/fimmu.2014.00478. View

20.

Chappell S, Edelman G, Mauro V . A 9-nt segment of a cellular mRNA can function as an internal ribosome entry site (IRES) and when present in linked multiple copies greatly enhances IRES activity. Proc Natl Acad Sci U S A. 2000; 97(4):1536-41. PMC: 26470. DOI: 10.1073/pnas.97.4.1536. View