Viral epitranscriptome

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The viral epitranscriptome includes all modifications to viral transcripts, studied by viral epitranscriptomics. Like the more general epitranscriptome, these modifications do not affect the sequence of the transcript, but rather have consequences on subsequent structures and functions.

Contents

History

The discovery of mRNA modifications dates back to 1957 with the discovery of the pseudouridine modification. [1] Many of these modifications were found in the noncoding regions of cellular RNA. Once these modifications were discovered in mRNA, discoveries in viral transcripts soon followed. [2] Detections have been aided with the advancement and use of new techniques such as m6A seq.

Mechanisms

Complexes

Viral RNA modifications use the same machinery as cellular RNA. This involves the use of "writer" and "reader" complexes. The writer complex contains the enzyme methyl transferase-like 3 (METTL3) and its cofactors like METTL14, WTP, KIAA1492 and RBM15/RBM15B which adds the m6A modification in the nucleus. [2] The family of proteins known as the YTH like YTHDC1 and YTHDC2 are capable of detecting these modifications within the nucleus. [3] In the cytoplasm, the reading duties are carried out by YTHDF1, YTHDF2, and YTHDF3. [2] The proteins ALKBH5 and FTO remove the m6A modification, functionally serving as erasers, with the latter having a more restricted selectivity depending on the position of the modification. [2]

N6-Methyladenosine (m6A)

This modification involves the addition of a methyl group (-CH3) group to the 6th nitrogen on the adenine base in an mRNA molecule. This was among the first mRNA modifications to be discovered in 1974. [4] This modification is common in viral mRNA transcripts and is found in nearly 25% of them. [5] The distribution of the modification not uniform with some transcripts containing more than 10. [2] m6A modifications are a dynamic process with many applications ranging from viral interactions with cellular machinery and structural adjustments to viral life cycle control. Studies have shown different regulatory patterns for different viruses depending on the context. For single stranded RNA viruses, the effects of the modifications appear to differ on the basis of the viral family. In the HIV-1 genome, the single stranded positive sense RNA contains m6A modifications at multiple sites in both the untranslated and coding regions. [6] The presence of this modifications in the viral transcript is enough to increase corresponding modifications in host cell mRNA through binding interactions between the HIV-1 gp 120 envelope protein, and the CD4 receptor in T lymphocytes without causing a corresponding increase in. [5] [7] For HIV-1 and other RNA viral families like chikungunya, enteroviruses and influenza, studies show both a positive and negative role for m6A modifications on viral life replication and infection. [5] For other families, the role effects are clearer. For the flaviridae family, the modification had a negative role and hindered viral replication. [8] The modification in respiratory syncytial virus families showed a positive role and enhanced viral replication and infection. [5] The causes of these apparently different roles from different responses within the same family of viruses and why the viral families like flaviridae conserve m6A modifications when they negatively impact their cycles are currently unknown and under investigation. [5]

Most of the RNA viruses carry out their cycles in the cytoplasm, away from the required machinery for writing and erasing m6A modifications which are housed in the nucleus. [5] For DNA viruses, that cycle in the nucleus with direct access to said machinery, no clear general positive or negative regulatory role can be attributed to m6A modifications. In the simian virus and hepatitis B viruses, different m6A reading complexes were shown to have different roles in regulation with some having a conserved positive role and others having a neutral or negative effect on replication.

O-methylation

This modification involves the addition of a methyl group to the 2' hydroxyl (-OH) group of the ribose sugar of RNA molecules. [9] In contrast with the m6A modification, it is the ribose sugar, a part of the backbone rather than the base that is altered. It is present in various kinds of cellular RNA, providing coding and structural support. 2-O-methylation of viral RNA is often accompanied by the addition of an inverted N-7methylguanosine to the 5' end on the phosphate group. [10] These modifications regulate important functions of viral RNA such as metabolism and immune system interactions.

Different viruses have their mechanisms for acquiring this modification. Cytoplasmic RNA viruses like flaviridae and coronaviruses encode the required to catalyze cap formation reactions, with some needing one enzyme for the 5' cap and 2-O-methylation while others require two enzymes like poxviruses. [11] Others, like influenza virus can hijack the methylguanosine caps from host cell mRNA and be preferentially translated. [10]

5-methylcytidine (m5C)

One viral epitranscriptome modification that has been identified is the 5-methylcytidine (m5C). HIV-1 and MLV transcriptomes contain elevated levels of these residues by approximately 14-30 fold when compared to a cell's normal levels. NSUN2 is the complex that codes the cytidine methyltransferases credited with m5C formation in cells and amplification in viral epitranscriptomes. The NSUN2 affects the translational aspect of the mRNA in the viral cells, boosting the expression of the viral genome. [12] It has also been found that the m5C alters the splicing pattern and locations in the viral transcriptome. This affected the HIV-1 transcript in both early and late infection. [13]

Immune system

Viral RNA modifications play important roles in interactions with the immune system of host cells. The m6A modification of viral RNAs allows for the viruses to escape recognition by the retinoic acid inducible gene-I receptor (RIG-I), in the type 1 IFN response, a crucial pathway of innate immunity. [5] 5' N-7methylguanisone capping and 2-O-methylation also play vital roles for the viral infections. The cap structures help viral RNA to blend in among modified cellular mRNA and avoid triggering immune response systems.

Related Research Articles

<span class="mw-page-title-main">HIV</span> Human retrovirus, cause of AIDS

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<span class="mw-page-title-main">Retrovirus</span> Family of viruses

A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. After invading a host cell's cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backward). The new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, transcribing and translating the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus. Many retroviruses cause serious diseases in humans, other mammals, and birds.

<i>Adenoviridae</i> Family of viruses

Adenoviruses are medium-sized, nonenveloped viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from their initial isolation from human adenoids in 1953.

<span class="mw-page-title-main">Kaposi's sarcoma-associated herpesvirus</span> Species of virus

Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ICTV) is Human gammaherpesvirus 8, or HHV-8 in short. Like other herpesviruses, its informal names are used interchangeably with its formal ICTV name. This virus causes Kaposi's sarcoma, a cancer commonly occurring in AIDS patients, as well as primary effusion lymphoma, HHV-8-associated multicentric Castleman's disease and KSHV inflammatory cytokine syndrome. It is one of seven currently known human cancer viruses, or oncoviruses. Even after many years since the discovery of KSHV/HHV8, there is no known cure for KSHV associated tumorigenesis.

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<span class="mw-page-title-main">Viral replication</span> Formation of biological viruses during the infection process

Viral replication is the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. Through the generation of abundant copies of its genome and packaging these copies, the virus continues infecting new hosts. Replication between viruses is greatly varied and depends on the type of genes involved in them. Most DNA viruses assemble in the nucleus while most RNA viruses develop solely in cytoplasm.

<span class="mw-page-title-main">RNA editing</span> Molecular process

RNA editing is a molecular process through which some cells can make discrete changes to specific nucleotide sequences within an RNA molecule after it has been generated by RNA polymerase. It occurs in all living organisms and is one of the most evolutionarily conserved properties of RNAs. RNA editing may include the insertion, deletion, and base substitution of nucleotides within the RNA molecule. RNA editing is relatively rare, with common forms of RNA processing not usually considered as editing. It can affect the activity, localization as well as stability of RNAs, and has been linked with human diseases.

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<span class="mw-page-title-main">Methyltransferase</span> Group of methylating enzymes

Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltransferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the leaving group and the methyl group attached to it acts as the electrophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA.

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<span class="mw-page-title-main">Virus</span> Infectious agent that replicates in cells

A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are found in almost every ecosystem on Earth and are the most numerous type of biological entity. Since Dmitri Ivanovsky's 1892 article describing a non-bacterial pathogen infecting tobacco plants and the discovery of the tobacco mosaic virus by Martinus Beijerinck in 1898, more than 11,000 of the millions of virus species have been described in detail. The study of viruses is known as virology, a subspeciality of microbiology.

<span class="mw-page-title-main">Rev (HIV)</span> HIV-1 regulating protein

Rev is a transactivating protein that is essential to the regulation of HIV-1 protein expression. A nuclear localization signal is encoded in the rev gene, which allows the Rev protein to be localized to the nucleus, where it is involved in the export of unspliced and incompletely spliced mRNAs. In the absence of Rev, mRNAs of the HIV-1 late (structural) genes are retained in the nucleus, preventing their translation.

<i>N</i><sup>6</sup>-Methyladenosine Modification in mRNA, DNA

N6-Methyladenosine (m6A) was originally identified and partially characterised in the 1970s, and is an abundant modification in mRNA and DNA. It is found within some viruses, and most eukaryotes including mammals, insects, plants and yeast. It is also found in tRNA, rRNA, and small nuclear RNA (snRNA) as well as several long non-coding RNA, such as Xist.

In molecular biology, the protein domain YTH refers to a member of the YTH family that has been shown to selectively remove transcripts of meiosis-specific genes expressed in mitotic cells. They also play a role in the epitranscriptome as reader proteins for m6A.

Within the field of molecular biology, the epitranscriptome includes all the biochemical modifications of the RNA within a cell. In analogy to epigenetics that describes "functionally relevant changes to the genome that do not involve a change in the nucleotide sequence", epitranscriptomics involves all functionally relevant changes to the transcriptome that do not involve a change in the ribonucleotide sequence. Thus, the epitranscriptome can be defined as the ensemble of such functionally relevant changes.

<span class="mw-page-title-main">Epigenetics of human herpesvirus latency</span>

Human herpes viruses, also known as HHVs, are part of a family of DNA viruses that cause several diseases in humans. One of the most notable functions of this virus family is their ability to enter a latent phase and lay dormant within animals for extended periods of time. The mechanism that controls this is very complex because expression of viral proteins during latency is decreased a great deal, meaning that the virus must have transcription of its genes repressed. There are many factors and mechanisms that control this process and epigenetics is one way this is accomplished. Epigenetics refers to persistent changes in expression patterns that are not caused by changes to the DNA sequence. This happens through mechanisms such as methylation and acetylation of histones, DNA methylation, and non-coding RNAs (ncRNA). Altering the acetylation of histones creates changes in expression by changing the binding affinity of histones to DNA, making it harder or easier for transcription machinery to access the DNA. Methyl and acetyl groups can also act as binding sites for transcription factors and enzymes that further modify histones or alter the DNA itself.

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

In epitranscriptomic sequencing, most methods focus on either (1) enrichment and purification of the modified RNA molecules before running on the RNA sequencer, or (2) improving or modifying bioinformatics analysis pipelines to call the modification peaks. Most methods have been adapted and optimized for mRNA molecules, except for modified bisulfite sequencing for profiling 5-methylcytidine which was optimized for tRNAs and rRNAs.

HSV epigenetics is the epigenetic modification of herpes simplex virus (HSV) genetic code.

<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.

Bryan Richard Cullen is a James B. Duke Professor of Molecular Genetics and Microbiology at Duke University Medical Center in Durham, North Carolina. Cullen was the Founding Director of the Duke University Center for Virology.

References

  1. ↑ Davis, Frank F.; Allen, Frank Worthington (August 1957). "Ribonucleic Acids from Yeast Which Contain a Fifth Nucleotide". Journal of Biological Chemistry. 227 (2): 907–915. doi: 10.1016/s0021-9258(18)70770-9 . ISSN   0021-9258. PMID   13463012.
  2. 1 2 3 4 5 Kennedy, Edward M.; Courtney, David G.; Tsai, Kevin; Cullen, Bryan R. (May 2017). Sullivan, Christopher S. (ed.). "Viral Epitranscriptomics". Journal of Virology. 91 (9). doi:10.1128/JVI.02263-16. ISSN   0022-538X. PMC   5391447 . PMID   28250115.
  3. ↑ Xiao, Wen; Adhikari, Samir; Dahal, Ujwal; Chen, Yu-Sheng; Hao, Ya-Juan; Sun, Bao-Fa; Sun, Hui-Ying; Li, Ang; Ping, Xiao-Li; Lai, Wei-Yi; Wang, Xing; Ma, Hai-Li; Huang, Chun-Min; Yang, Ying; Huang, Niu (February 2016). "Nuclear m 6 A Reader YTHDC1 Regulates mRNA Splicing". Molecular Cell. 61 (4): 507–519. doi: 10.1016/j.molcel.2016.01.012 . ISSN   1097-2765. PMID   26876937.
  4. ↑ Desrosiers, Ronald; Friderici, Karen; Rottman, Fritz (October 1974). "Identification of Methylated Nucleosides in Messenger RNA from Novikoff Hepatoma Cells". Proceedings of the National Academy of Sciences. 71 (10): 3971–3975. Bibcode:1974PNAS...71.3971D. doi: 10.1073/pnas.71.10.3971 . ISSN   0027-8424. PMC   434308 . PMID   4372599.
  5. 1 2 3 4 5 6 7 Baquero-Perez, Belinda; Geers, Daryl; Díez, Juana (2021-06-01). "From A to m6A: The Emerging Viral Epitranscriptome". Viruses. 13 (6): 1049. doi: 10.3390/v13061049 . ISSN   1999-4915. PMC   8227502 . PMID   34205979.
  6. ↑ Lichinchi, Gianluigi; Gao, Shang; Saletore, Yogesh; Gonzalez, Gwendolyn Michelle; Bansal, Vikas; Wang, Yinsheng; Mason, Christopher E.; Rana, Tariq M. (2016-02-22). "Dynamics of the human and viral m6A RNA methylomes during HIV-1 infection of T cells". Nature Microbiology. 1 (4): 16011. doi:10.1038/nmicrobiol.2016.11. ISSN   2058-5276. PMC   6053355 . PMID   27572442.
  7. ↑ Tirumuru, Nagaraja; Wu, Li (March 2019). "HIV-1 envelope proteins up-regulate N6-methyladenosine levels of cellular RNA independently of viral replication". Journal of Biological Chemistry. 294 (9): 3249–3260. doi: 10.1074/jbc.ra118.005608 . ISSN   0021-9258. PMC   6398121 . PMID   30617182.
  8. ↑ Gokhale, Nandan S.; McIntyre, Alexa B.R.; McFadden, Michael J.; Roder, Allison E.; Kennedy, Edward M.; Gandara, Jorge A.; Hopcraft, Sharon E.; Quicke, Kendra M.; Vazquez, Christine; Willer, Jason; Ilkayeva, Olga R.; Law, Brittany A.; Holley, Christopher L.; Garcia-Blanco, Mariano A.; Evans, Matthew J. (November 2016). "N6 -Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection". Cell Host & Microbe. 20 (5): 654–665. doi:10.1016/j.chom.2016.09.015. ISSN   1931-3128. PMC   5123813 . PMID   27773535.
  9. ↑ Dimitrova, Dilyana G.; Teysset, Laure; Carré, Clément (2019-02-05). "RNA 2'-O-Methylation (Nm) Modification in Human Diseases". Genes. 10 (2): 117. doi: 10.3390/genes10020117 . ISSN   2073-4425. PMC   6409641 . PMID   30764532.
  10. 1 2 Ribeiro, Diana Roberta; Nunes, Alexandre; Ribeiro, Daniela; Soares, Ana Raquel (2023-08-01). "The hidden RNA code: implications of the RNA epitranscriptome in the context of viral infections". Frontiers in Genetics. 14. doi: 10.3389/fgene.2023.1245683 . ISSN   1664-8021. PMC   10443596 . PMID   37614818.
  11. ↑ Hyde, Jennifer L.; Diamond, Michael S. (May 2015). "Innate immune restriction and antagonism of viral RNA lacking 2׳-O methylation". Virology. 479: 66–74. doi:10.1016/j.virol.2015.01.019. PMC   4424151 . PMID   25682435.
  12. ↑ Tsai, Kevin; Cullen, Bryan R. (October 2020). "Epigenetic and epitranscriptomic regulation of viral replication". Nature Reviews Microbiology. 18 (10): 559–570. doi:10.1038/s41579-020-0382-3. ISSN   1740-1534. PMC   7291935 . PMID   32533130.
  13. ↑ Courtney, David G. (May 2021). "Post-Transcriptional Regulation of Viral RNA through Epitranscriptional Modification". Cells. 10 (5): 1129. doi: 10.3390/cells10051129 . ISSN   2073-4409. PMC   8151693 . PMID   34066974.
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