https://orcid.org/0000-0002-7320-435X
ABSTRACT
The process of protein post-translational modifications (PTM) is one of the critical mechanisms of regulation of many cellular processes, which makes it an attractive target for various viruses. Since viruses cannot replicate on their own, they have developed unique abilities to alter metabolic and signaling cell pathways, including protein PTMs, to ensure faithful replication of their genomes. This review describes several ways of how lysine-specific PTMs are used by various viruses to ensure its successful invasion and replication. Covalent modifications like acetylation, ubiquitination, and methylation form a complex system of reversible and often competing modifications, which adds an additional level of complexity to the system of regulation of the activity of host proteins involved in viral replication and propagation. In furthering these, we also describe the manner in which PTM pathways can also be accosted by various types of viruses to neutralize the host’s cellular mechanisms for anti-viral protection and highlight key areas for future therapeutic targeting and design.
Introduction
It is widely accepted that viruses use the host’s cellular resources for their replication and propagation. Since these processes are heavily regulated by Post-Translational Modification (PTM) of proteins it is interesting how the cascades of various PTMs are implemented at all stages of viral development. The modifications of positively charged amino acids (such as arginine and lysine) play an important role in the regulation of folding and biochemical activity of cellular proteins, PTMs such as ubiquitination, sumoylation, acetylation, methylation, therefore introduce an additional level of intracellular regulation for cellular signaling proteins. For example, lysine-specific modifications that target proteins affect key cellular processes such as proteasome degradation [Citation1,Citation2], repair of double-strand DNA breaks [Citation3–Citation6], regulation of gene expression [Citation7,Citation8] [Citation9–Citation13], signaling pathways [Citation14–Citation18] immune response [Citation19,Citation20], cell cycle [Citation21,Citation22] and metabolism [Citation23,Citation24].
Using cellular PTM systems, at each stage of their replication cycle, viruses therefore can affect the steady-state dynamics for ubiquitination, acetylation, and methylation of cellular proteins and potentially disrupt the metabolic and signaling pathways of the host cells to ensure successful production of viral particles. This review focuses on the importance of such events in the context of how viruses alter the biology of host cells and which ones have particular importance in the development of disease, thereby suggesting novel potential targets for therapeutic development.
Post-translational modifications overview
Acetylation
Acetylation is one of the commonest post-translational modifications for proteins and is derived from the transfer of the acetyl group from acetyl coenzyme A (Ac-CoA) to the host protein. Broadly, this can be divided into the amino-terminal protein acetylation, driven by N-terminal acetyltransferases or NATs, and general acetylation at the post-translational or co-translational level of lysine residues, performed by Lysine AcetylTransferases or KATs (initially referred as Histone AcetylTransferases or HATs). Mechanistically, the extremely delicate balance between acetylation and deacetylation of a protein is maintained by the respective activity of the NATs or KATs (HATs) () and lysine deacetylases or KDAC (HDAC) enzymes (). Whereas the number of KAT enzymes is relatively small, they do have a fairly wide range of substrates due to them functioning as part of large protein complexes that can regulate and coordinate KAT activity, localization and substrate specificity [Citation25].
Table 1. Types of human acetyltransferases and members of KAT (HAT) families.
Table 2. Types of human KDACs (HDACs) and their cellular localization.
Ubiquitination
Ubiquitination is the post-translational covalent addition of one or more ubiquitin groups or so-called ubiquitin-like modifiers (SUMO, NEDD8, ISG15, FAT10, ATG8, ATG12 and URM1 [Citation26]) to the side chain amino acid groups of the target protein by the ubiquitin ligase enzymes. Ubiquitin is attached to the ε-amino group of the lysine residue through its C-terminal glycine residue by an E1-E2-E3 multi-enzyme cascade. A wide spectrum of ubiquitinated target substrates is achieved specifically due to the diverse number of E3-ligases, which usually target a specific protein. The K48-linked polyubiquitination is of particular interest as it targets substrate proteins for proteasomal degradation. Moreover, Lys K63-linked ubiquitin polymers [Citation27], as well as K6, K11, K27, and K29 ubiquitination have also been described [Citation28]. Deubiquitinylation processes are in turn carried out by five different classes of deubiquitinating isopeptidases or deubiquitinases (DUBs). To date, five families of DUBs have been described-UCHs (ubiquitin C-terminal hydrolases), USPs (ubiquitin-specific proteases), OUTs (ovarian tumor associated), MJD (Machado-Joseph disease associated) and JAMM (Jab1/Mpn/Mov34).
Methylation
Methylation is broadly understood as the addition of one or several methyl groups to carbon, oxygen, nitrogen, sulfur and even halides made by a special class of enzymes called methyltransferases (MTases), which use S-adenosylmethionine (SAM, also known as Ado-Met) as the donor of methyl groups. Five different classes of SAM-dependent methyltransferases exist with members differing in structural organization [Citation29], each class having its own substrate specificity. From all of the MTases, it is the methyltransferases from classes I, III and IV which possess the ability to methylate proteins [Citation30]. In turn, each of the members of these protein methyltransferases differ in the type of amino acid residue they methylate (lysine or arginine) in addition to the numbers of methyl groups transferred.
Viruses can hijack the cellular post-translational modification machinery
Since PTMs play a key role in the regulation of important cellular processes, in this part of the review we will discuss the basic ways in which the mostly well-studied viruses exploit the PTM enzymatic machinery of the host cell at the different phases of viral replication ().
Table 3. Post-translational modifications of cellular proteins beneficial for virus survival with cellular and viral proteins involved.
The importance of acetylation in viral entry and cellular transport of virus particles
After entering the cell, one of the hallmarks of viral movement through the cell to reach their replication site is characterized by a change of cytoskeleton structure. For example, a significant amount of data confirms that HIV-1 utilizes the microtubule-based transport to deliver its genetic material from the cell’s periphery to the nucleus. The exact mechanism of this process is not well established. However, it was shown that the interaction between the HIV gp120 protein and the CD4 T-cell surface receptor induces microtubule stabilization [Citation31]. Microtubule stability is mediated by α-tubulin posttranslational modifications, including acetylation, which is, in turn, recognized by specific motor proteins. Sabo et al. [Citation32] showed that HIV-1 infection augmented the acetylation of microtubules (MT) mediated through an interaction with an EB1 protein. The latter regulates MT stabilization via the recruitment of MT plus-end tracking proteins (+TIPs). HIV-1 matrix protein (MA), a component of incoming viral particles and of the Gag poly-protein, was also shown to target the EB1-binding protein, Kif4 to induce the MT stabilization. The importance of tubulin acetylation is supported by the fact that HDAC6 deacetylates tubulin and thereby suppresses infection by HIV-1 [Citation33]. Similarly, binding of Kaposi’s sarcoma-associated herpesvirus or human herpesvirus 8 (HHV-8) glycoprotein gB to α3β1 integrin induces the activation of the RhoA/mDia2 pathway promoting the stabilization and subsequent acetylation of MT. The latter event results in subsequent transport of viral particles through the microtubules in the retrograde direction to the microtubule organization center (MTOC), which is adjacent to the nucleus. Using this mechanism the viral genetic material is delivered to its replication site [Citation34]. However, the direct contribution of HHV-8-induced signaling pathways to the acetylation of α-tubulin is not fully described. Conversely, Avdoshina et al. [Citation35] showed that after HIV enters nerve cells its gp120 protein actually reduces the degree of microtubule polymerization and α-tubulin acetylation, which resulted in destabilization of the cytoskeleton and deregulation of its structural functions. It is believed that HIV changes the structure of the cytoskeleton (largely due to the regulation of α-tubulin acetylation level), but the exact consequence of that depends on the type of cell being infected.
In addition to cytoskeletal reorganization, minutes after HIV entry, the amount of CD4 receptor on the surface of infected cells was also seen to be down-regulated, to limit the entry of additional viral particles. Binding of viral ligand to CD4 also diminished, preventing newly synthesized virus particles from leaving the host cell [Citation36]. This was due to the targeting the CD4 for proteasomal degradation by the viral Vpu protein in conjunction with host’s activity of the E3-ubiquitin ligase complex consisting of the Skp1, Cullin1 and βTrCP proteins [Citation37]. Such a mechanism is quite common among a number of viruses and represents a convenient tool for altering key cellular signaling pathways and hence overcoming cellular antiviral protection systems. A large enough group of viruses including Ectromelia virus (ECTV), Human Papillomavirus (HPV), KSHV, and many others hijack the members of the Cullin-RING E3 Ligase family (CRL). These enzymes are responsible for exchanging ~20% of ubiquitinated proteins, which makes them an attractive tool for the virus to avoid the host’s immune response [Citation38]
The Ectromelia virus (ECTV) infected dendritic cells and macrophages also show a significant level of α-tubulin acetylation, causing its stabilization and thus reducing microtubule mobility when compared to healthy cells. It is assumed that such changes allow ECTV to move around the cell at both initial and late stages of infection, which contributes to its efficient replication and the rapid delivery of ready-made virus particles to the plasma membrane for their release [Citation39]. Interestingly, microtubule-derived α-tubulin K40 acetylated sites serve as pool of human parainfluenza type III virus (HPIV3) inclusion bodies made up of viral nucleoprotein N in complex with the viral RNA and RNA-dependent RNA polymerase. In support of these, Zhang et al. [Citation40] showed that acetylated α-tubulin promoted the aggregation of these inclusion bodies resulting in the formation of viroplasm, a major center for the synthesis of viral RNA in the absence of HPIV3 promoting tubulin acetylation.
Ubiqitination and its interplay with acetylation in neutralization of cellular antiviral defense mechanisms
One of the main challenges for a virus throughout its life cycle is to neutralize the cellular mechanisms of antiviral protection. This is often resolved by disrupting the NF-κB signaling pathway which controls the inflammatory/immune response, gene expression, apoptosis and cell cycle regulation as utilized effectively by the poxviruses. Thus, the vaccinia virus (VACV) K1 protein disrupts the acetylation of NF-κB subunit, RelA (p65) by reducing RelA–CBP/p300 interactions, abolishing its binding to the promoter of the genes involved in regulating the immune response [Citation41]. Ning et al. [Citation42] showed that with the help of the 002 protein, the Orf virus inhibits RelA acetylation thus preventing RelA Ser276 phosphorylation which effectively dampens p300 and CBP co-activators binding. A similar phenomenon was observed in high-risk human papillomaviruses (hrHPV). It has been shown that keratinocytes infected with hrHPV exhibit a reduced level of lysine K310 RelA acetylation and as a result show reduced expression of pro-inflammatory cytokines and a generally less pronounced immune response. This effect is achieved due to the epidermal growth factor receptor (EGFR) activation and subsequent increase in expression of the interferon-binding development regulator 1 (IFRD1), which suppresses RelA transcriptional activity due to the formation of trimolecular IFRD1-RelA-HDAC3 complexes resulting in RelA deacetylation [Citation43]. It is important to note that EGFR mutations with increased activity and overexpression are associated with a high risk of tumor development [Citation44] and is a phenomenon associated with the high oncogenicity of several viruses. Finally, in response to a viral infection, the group of ECTV proteins EVM002, EVM005, EVM154, and EVM165 are able to interact with the Skp1 component of the E3 SCF-ubiquitin ligase complex and disrupt the operation of such a complex. The target of SCF is IκBα, an inhibitor of the NF-κB transcription factor, and thus, the inhibition of the proteasomal degradation of IκBα leads to lowered gene expression by NF-kB and a lower immune response [Citation45].
Another target of viruses is transcriptional factor and tumor suppressor p53, which also induces various signaling pathways that modulate immunity, viral infections, cell cycle arrest and apoptosis. Therefore, some viruses that disrupt p53 activity interfere with cell cycle regulation, which helps them to ensure their own efficient replication and survival. DNA viruses manage this by creating double-stranded DNA breaks (DBS) in the nucleus for replication purposes, which inevitably causes a DNA damage response (DDR) and p53 activation [Citation46]. The latter event leads to cell cycle arrest and apoptosis. To avoid the blockage of proliferation and cell death during the HPV infection, the hrHPV E6 protein attracts E3-ubiquitin ligase E6AP, which directs p53 for proteasomal degradation, thereby allowing the virus to replicate without causing apoptosis [Citation47]. Oncogenic Epstein-Barr virus (EBV) also induces the proteasomal degradation of p53, allowing for its successful replication. Furthermore, the EBNA3C viral protein stabilizes the ubiquitin ligase Mdm2 thus giving increased Mdm2 activity towards p53, which in turn enhances p53 ubiquitination and its proteasomal degradation [Citation48].
Similarly, some viral proteins can also modulate cell cycle arrest proteins through their ability to modulate DUB activity. For example, the EBV EBNA1 protein is involved in initiation of viral DNA replication, transcriptional activation of some viral protein synthesis and mitotic segregation of EBV. It binds to HAUSP/USP7 deubiquitinase which also acts upon p53. Formation of an HAUSP/USP7-EBNA1 complex disrupts the interaction between HAUSP/UPS and p53, which leads to enhanced p53 proteasomal degradation [Citation49]. Adenovirus type V (Ad5) reduces the level of both p53 protein and its transcription activity. It was shown that Ad5 E1B55K and E4orf6 proteins cooperate to target p53 for proteasomal degradation with the help of E3 ubiquitin ligase complex composed of Cullin family member Cul5, Elongins B and C, and the RING-H2 finger protein Rbx1(ROC1) [Citation50]. Further, in the situation when E1B was mutant the adenovirus E1A protein blocked the p300-dependent acetylation of p53 at K382 and reduced the amount of promoter-bound Sp1 transcription factor, thereby disrupting its transcriptional activity towards its target genes, in particular p21/WAF1/CIP. The latter is one of the critical inhibitors of CDK2, a cell cycle-dependent kinase required for G1/S progression. As a result, the E1A protein prevented cell cycle arrest [Citation51]. Recently, Dutta et al. reported that HPV E6 interacted with a DUB, USP46, facilitating its interaction with and de-ubiquitination of a ubiquitin ligase Cdt2. As Cdt2 becomes stabilized, it ubiquitinates and degrades Set8 and p21 proteins, thus promoting cell proliferation [Citation52].
There are contradictory data on the effect of IAV on the stability and function of p53 as Wang et al. [Citation53] showed that viral nucleoprotein NP binds to p53 in such a way that it disrupts the interaction of p53 with Mdm2, therefore stabilizing p53. Nailwal et al. [Citation54] showed that NP reduces the level of RNF43 ubiquitinase, whose target is also p53, thereby increasing steady-state protein levels of p53. This is consistent with the fact that, as a cytolytic virus, IAV induces apoptosis in various cell types [Citation55]. However, there are observations that conflict with these data, where a decrease in the activity (or amount) of the p53 protein in IAV infected cells has been seen [Citation53]. These mechanistic proposals for the regulation of p53 activity regulation during influenza A virus infection could therefore be more complex than originally thought.
HBV was also reported to disrupt the p53 pathway. Its onco-protein HBx can bind to the C-terminus of p53 and block p53-mediated apoptosis, thereby contributing to hepatocarcinogenesis [Citation56].
By analogy, other key anti-viral mammalian proteins are also gaining significant attention, highlighting the importance of PTM pathways, which give viral replication a distinct survival advantage. For example, the role of Nt-acetylation during IAV infection has also been described [Citation57], where IAV PA polymerase was observed to undergo Nt-acetylation by NatB, and possibly by other Nt-acetyltransferases with the outcome of enhancing the viral polymerase protein activity.
Alternatively, mechanisms allowing the virus to avoid the cellular immune response have also been explored with very interesting outcomes. For example, the E7 protein of HPV has been shown to positively modulate retinoblastoma protein (pRb) proteasomal degradation [Citation58], thus promoting the G1/S transition of the cell cycle (through E2F release) and which allows infected cells to avoid cell cycle arrest [Citation59]. E2F1 also interacts with Set7/9 methyltransferase which can in turn, complex with the ubiquitin ligase Mdm2 resulting in augmentation of cyclin E expression. At the same time, Set7/9 prevents Mdm2-mediated degradation of p53 and affects cell cycle arrest and apoptosis [Citation60,Citation61]. The balance between the transcriptional effects of Set7/9 on E2F1 and p53 is likely to be cell context-dependent. Similarly, the potentiating effects of Set7/9 on transcription have also been seen to enhance transcription of HIV where Set7/9 methylates the viral activator protein TAT [Citation62].
Another mechanism by which HPV avoids apoptosis and suppression of its replication has been described by Dutta et al. [Citation63]. A histone acetyltransferase, TIP60, acetylates histone H4 in the promoter of HPV E6 gene to recruit the Brd4 transcription repressor. However, both low- and high-risk HPV isoforms of the E6 protein in turn, was able to down-regulate TIP60 by priming it for proteasomal degradation, thereby relieving its own promoter from the repression. The latter event also caused down-regulation of p53, which was degraded by HPV E6 proteins [Citation64]. Although the authors convincingly showed that E6 was able to direct TIP60 to proteasomal degradation, yet they did not provide any indication to which particular ubiquitin ligase was involved in this process.
Of note, the TIP60 activity is regulated by several HPV-induced signaling pathways, as it is necessary for differentiation-dependent viral genome amplification. For instance, Tip60 levels were increased in cells stably maintaining complete HPV episomes. For example, a transcription factor, STAT5, activated by viral proteins, acts through GSK3β kinase to regulate Tip60 activation. It indicates that effects of HPV on the life cycle of infected cells seem more complicated than originally thought [Citation65].
As a novel regulatory mechanism, there have also been recent reports of cellular deubiquitinating (DUB) enzymes negatively affecting antiviral immune signaling pathways to enhance viral replication. Helicase RIG-I belongs to the retinoic acid-inducible gene I-like receptor (RLR) family, which recognizes single/double-stranded RNA and can be activated upon N-terminal 63K polyubiquitination [Citation66]. As a key regulator of this step, cellular DUB USP14 has been shown to directly deubiquitinylate RIG-I, which has the effect of enhancing the replication of vesicular stomatitis virus (VSV) [Citation67]. Similarly, DUB USP19 promotes replication of enterovirus type 71 (EV71) by removing the K63 polyubiquitin chains from TRAF3 (thereby suppressing cellular type I IFN-γ signaling) [Citation68] and deubiquitinating Beclin-1, which leads to the activation of autophagy and subsequent inhibition of TBK1/IRF3 activation and the immune response [Citation69]. Moreover, USP13 catalyzes STING deubiquitination, which abolishes its kinase activity towards the IRF3 transcription factor and which ultimately leads to the disruption of the immune response at the gene expression level. Such a molecular dynamic is supported by USP13 deficiency, which has been shown to impair herpes simplex virus (HSV) replication [Citation63]. Similar mechanisms for antiviral immune response regulation have also described for CYLD, USP3, USP13, USP20, USP21, OTUB1, and OTUB2 DUBs [Citation70].
Methylation and acetylation in transition between latent and lytic state
An interesting example of viral adaptation to cellular changing conditions is its ability to switch between lytic and latent phases. This change is made by manipulating epigenetic post-translational modifications. Thus, the cellular protein HCF-1 is part of the enhancer nuclear complex (EC) and is necessary for the transcription of early α-herpesvirus genes while in its lytic state. Additionally, it can also act as a scaffolding protein for the binding of various modulators of chromatin structure, such as methyltransferases, demethylases, and acetyltransferase. This leads to the suppression of heterochromatin formation via the virally induced H3K9-met demethylation and the emergence of pro-transcriptional modifications as with H3K4-me.
In light of these observations, an interesting example of how viruses maintain their latent state and the mechanisms that permit exit from this is highlighted by KSHV [Citation71]. In this instance, the viral genome exists in a bivalent state and is enriched with both repressive (H3K9me3 and H3K27me3) and activating (acH3 and H3K4me3) forms. Bivalent and activating transcriptional modifications are regulated in the area of immediate early (IE) and early (E) gene expression. By contrast, the activating modifications which attract transcriptionally active RNA polymerase II are located exclusively within the region of latency-associated genes (La) to ensure their continuous expression resulting in the expression of the latency-associated transcript (LAT) which is necessary to maintain latent state. Consequently, under certain stimuli, activation of the lytic phase is initiated with the assistance of the viral RTA protein. Here, the cellular H3K27me3 demethylases JMJD3 and UTX are activated, which permit active H3K4me3 to modify the RTA promoter. Newly synthesized RTA protein binds to its own promoter, sequestering KAT, which leads to the large-scale activation of chromatin remodeling and continuation of the lytic phase [Citation72].
By comparison, retroviruses face a more difficult task because they need to integrate into the host’s genome for successful replication. To do so, they need to change the structure of chromatin locally from a transcriptionally inactive to an active state, which is often achieved by an increased level of acetylation of various sections of histones. For example, at the first step of the HIV genome integration viral protein Tat and cellular activating transcription factors NF-κB p65, AP-1, Myb, GR C/EBP, NFAT, Ets-1, LEF-1, and IRF sequester KATs such as CBP, GCN5, and P/CAF to the LTR-specific viral DNA sequence (a region necessary for the insertion of viral genetic material into the host genome) [Citation73]. This leads to increased histone-H3 and -H4 acetylation in the whole region surrounding the LTR and, as a result, increased availability of cellular DNA. The localization of KAT to the integration site is also important for acetylation of the viral integrase, since this increases its affinity for DNA [Citation74] and for the activation of the important viral transcription factor Tat. Alternatively, non-acetylated Tat can bind CBP/p300 and cdk9/cyclin T complexes, which facilitate the initiation of transcription within the LTR. Upon acetylation of Tat, it can mediate the binding of bromdomain-containing chromatin-modifying complexes which facilitate transcriptional elongation [Citation75].
With HIV, KDACs were shown to play a central role in regulating the latent state of the virus. Cell transcription factors such as Ying-Yang 1 (YY1), late SV40 factor (LSF), COUP-TF interacting protein (CTIP2), c-promoter-binding factor (CBF-1), NF-κB p50 homodimer, c-myc and Sp1, having a considerable homology between its DNA binding sequences and HIV-1 initiator region, are all capable of sequestering HDAC1, HDAC2 and HDAC3 to the HIV promoter, which ultimately cause termination of viral protein transcription and viral latency [Citation76]. A distinctive feature of viral latency is also the presence of the Nuc-1 nucleosome, which is associated with the site located immediately downstream of the HIV promoter. Reactivation of HIV transcription is thought to be connected with the removal of Nuc-1 from this site, which is believed to be mediated upon deacetylation of Nuc-1.
Methyltransferases which also regulate the latent or lytic phases of viruses have also received much attention. For example, it was shown that H3R26 methylation by methyltransferase CARM1 is important for maintaining the latent state as it creates a negative feedback loop with H3K27 acetylation, which in turn contributes to H3R26 methylation and to viral and cellular genome transcription [Citation77]. Additionally, H3K9 me2/3 and H3K27me3 are also evident in the latent phase of the virus [Citation76], as well as H4K20me1 [Citation78].
While integrating its DNA in the genome of the cell, HPV can also interact with chromatin modulators through its oncoproteins E6 and E7, which modulate various KAT, KDAC, HMT and chromatin remodeling complexes, which presents an interesting regulatory mechanism. Among their binding partners are p300 and p300/CBP which are capable of acetylating all four histone proteins. The interaction of PCAF histone acetyltransferase with E7 disrupts IL-8 promoter transcriptional activation, which has the effect of down-regulating the cellular immune response to infection. Additionally, E6 downregulate the activity of CARM1, PRMT1, and SET7 methyltransferases, which are required for methylation of p53-responsive promoters and stabilization of p53 by p53K372 mono-methylation, thereby suppressing p53 signaling [Citation79], which can eventually lead to cancer development. Moreover, the HPV16 E7 protein was shown to assosiate with the E2F6 protein to abrogate its repressive activity on E2F6 target genes. The E2F6 transcription factor is also a part of several polycomb repressive compexes (PRCs) that globally regulate transcriptional competence of genes. Such PRCs components as BMI1, PCGF2 (MEL-18), CBX4 (hPC2), RING1, MGA, and L3MBTL2b were also shown to be associated with E7. These data suggest that HPV16 might regulate chromatin dynamics through interactions with Polycomb complexes [Citation80]. Lastly, mounting evidence suggests that HPV can actively change the structure of the host genome, giving rise to genomic instability and may contribute to the oncogenicity of some types of viruses [Citation81].
Recently, p300-induced acetylation of K111 in the HPV protein E2 was shown to be crucial for HPV replication. Acetylation of the particular K111 has turned out to be necessary for Topo1 recruitment to the viral origin to remove the replication-inhibitory DNA supercoiling arising from the HPV E1 protein helicase activity [Citation82]. Importantly, the K111R mutant failed to maintain episomes and integrate into host chromosomes. The authors suggested that p300-mediated acetylation of K111 in the E2 protein might also act as a switch from the maintenance replication to vegetative amplification.
Conclusion
Currently, the extensive involvement of viruses with the PTM system of infected cells is growing as an area of intense scientific interest, as highlighted through a number of key publications over the last few years. Consequently, such contributions have added to a detailed understanding of the general mechanisms of viral replication while facilitating a strong basis on which to base a rational search for potential targets for antiviral therapy. In this clinical context, some milestones have already been achieved. For example, Zhang [Citation83] described the protein inhibitors of deubiquitinases of the Middle East respiratory syndrome-related coronavirus (MERS-CoV) and the Crimean-Congo hemorrhagic fever virus. The use of such inhibitors allowed almost complete suppression with great efficacy on the development and spread of infection.
From such studies has arisen another promising area of treatment for Epstein-Barr virus-derived cancers through the design and characterization of various cellular HDAC inhibitors which facilitates the transition of the virus from the latent phase to the lytic phase, predisposing it to further antiviral therapy [Citation84–Citation86]. Of these, several low molecular weight EGFR inhibitors with potential antiviral activity have emerged, including CI-1033 (Canertinib), gefitinib (IressaTM), PD153035, vandetanib and erlotinib [Citation87].
More recently, Kim et al. [Citation88] have also highlighted a Poly6 hexapeptide, which is derived from the DNA polymerase of the hepatitis B virus and which can prevent the development of HIV infection, mainly through the suppression of HIV integrase activity. This effect is achieved upon reducing the expression of cellular acetyltransferase p300, one of the cofactors of HIV integrase.
While many published studies do not describe the precise molecular mechanisms by which viruses hijack one or another pathway of the PTM cellular system, future studies should light to this important question so that a targeted approach can be adopted in the search for candidate targets for anti-viral drugs.
Acknowledgments
The authors acknowledge the support of RFBR grant #18-29-09144 мк and the grant from the Russian Government Program for the Recruitment of the leading scientists into the Russian Institutions of Higher Education 14. W03.31.0029 to N.B. and M. P.
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No potential conflict of interest was reported by the authors.
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