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• W2511381211 abstract "Polyamines play important roles in a range of cellular processes. In this issue of Cell Host & Microbe, Mounce et al., 2016Mounce B.C. Poirier E.Z. Passoni G. Simon-Loriere E. Cesaro T. Prot M. Stapleford K.A. Moratorio G. Sakuntabhai A. Levraud J.P. Vignuzzi M. Cell Host Microbe. 2016; 20 (this issue): 167-177Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar link polyamine metabolism to the interferon response and demonstrate proviral effects for polyamines. The study points to the pathway as a potential novel pan-viral therapeutic target. Polyamines play important roles in a range of cellular processes. In this issue of Cell Host & Microbe, Mounce et al., 2016Mounce B.C. Poirier E.Z. Passoni G. Simon-Loriere E. Cesaro T. Prot M. Stapleford K.A. Moratorio G. Sakuntabhai A. Levraud J.P. Vignuzzi M. Cell Host Microbe. 2016; 20 (this issue): 167-177Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar link polyamine metabolism to the interferon response and demonstrate proviral effects for polyamines. The study points to the pathway as a potential novel pan-viral therapeutic target. Polyamines are small aliphatic polycations that bind nucleic acids and proteins. The enzymes involved in polyamine synthesis and catabolism are conserved across all kingdoms of life, and their expression and activities are tightly regulated. The canonical pathway is depicted in Figure 1 (Pegg, 2016Pegg A.E. J. Biol. Chem. 2016; 291: 14904-14912Crossref PubMed Scopus (347) Google Scholar). Polyamines are important for a number of cellular functions, such as transcription, translation, the cell cycle, and stress responses, and when dysregulated they are associated with cancer, aging, and neurodegenerative diseases (Miller-Fleming et al., 2015Miller-Fleming L. Olin-Sandoval V. Campbell K. Ralser M. J. Mol. Biol. 2015; 427: 3389-3406Crossref PubMed Scopus (394) Google Scholar). The enzymes in the polyamine metabolism pathway that are extensively studied share several interesting features. The activity and expression of these enzymes are regulated by multiple creative mechanisms in response to polyamine levels and cellular cues (Miller-Fleming et al., 2015Miller-Fleming L. Olin-Sandoval V. Campbell K. Ralser M. J. Mol. Biol. 2015; 427: 3389-3406Crossref PubMed Scopus (394) Google Scholar). On the transcriptional level, the human spermidine/spermine-N1-acetyltransferase 1 (SAT1) gene contains a 5′ polyamine-responsive element that controls expression in a polyamine-dependent manner. Moreover, in the presence of high polyamine levels, formation of an alternatively spliced variant of SAT1 that is normally targeted by nonsense-mediated mRNA decay is reduced, leading to an increase in SAT1 activity and lowered polyamine levels. On the translational level, upstream open reading frames in the 5′ UTR of the mRNAs encoding SAT1 and ornithine decarboxylase (ODC), an enzyme that decarboxylates ornithine to form putrescine, regulate their translation efficiency. ODC also interacts with an antienzyme upon increased polyamine levels, resulting in a conformational change in ODC that targets it for proteasomal degradation, which is an example of post-translational regulation. Furthermore, enzymes such as ODC, SAT1, and S-adenosylmethionine decarboxylase (AdoMetDC) get turned over rapidly, which facilitates their fluctuations in response to polyamine concentrations. Since polyamines are known to interact with nucleic acids, one can imagine that they can also interact with viral genomes and play a role in viral replication and translation. Previous studies that examined the effects of polyamines on herpes simplex virus infection showed that they are incorporated into virions and positively affect DNA synthesis (Pohjanpelto et al., 1988Pohjanpelto P. Sekki A. Hukkanen V. von Bonsdorff C.H. Life Sci. 1988; 42: 2011-2018Crossref PubMed Scopus (14) Google Scholar, Raina et al., 1981Raina A. Tuomi K. Mäntyjärvi R. Med. Biol. 1981; 59: 428-432PubMed Google Scholar). However, the effects of polyamines on the life cycle of RNA viruses are unclear. For example, when two alphaviruses were tested, polyamine depletion was found to inhibit the production of Semliki Forest virus, but not Sindbis virus, although Sindbis viral replication was delayed (Pohjanpelto et al., 1988Pohjanpelto P. Sekki A. Hukkanen V. von Bonsdorff C.H. Life Sci. 1988; 42: 2011-2018Crossref PubMed Scopus (14) Google Scholar, Raina et al., 1981Raina A. Tuomi K. Mäntyjärvi R. Med. Biol. 1981; 59: 428-432PubMed Google Scholar). Much remains to be learned about the role of polyamines in virus replication and the cellular response to infection. Vertebrates have evolved a sophisticated innate immune response to fight viral infections. Recognition of viral nucleic acids and glycoproteins activate interferon (IFN)-regulatory factors 3 or 7, leading to their dimerization and nuclear translocation and expression of type I IFN genes (Schneider et al., 2014Schneider W.M. Chevillotte M.D. Rice C.M. Annu. Rev. Immunol. 2014; 32: 513-545Crossref PubMed Scopus (1728) Google Scholar). Type I IFN receptor binding of IFN activates JAK/STAT signaling, which results in the upregulation of several hundreds of IFN-stimulated genes (ISGs) with antiviral activities that target various stages of the viral life cycle. However, positive-sense RNA viruses are equipped with diverse strategies to counteract the action of IFN (Ma and Suthar, 2015Ma D.Y. Suthar M.S. Curr. Opin. Virol. 2015; 12: 26-37Crossref PubMed Scopus (39) Google Scholar). Interestingly, the polyamine regulatory enzyme SAT1 has been found to be upregulated by IFN signaling, although the role that this enzyme plays in the IFN response remained obscure. In this issue of Cell Host and Microbe, Mounce and colleagues demonstrate that polyamines can promote RNA-dependent RNA replication and are required for the replication of the alphavirus chikungunya (CHIKV) and the flavivirus Zika (ZIKV) (Mounce et al., 2016Mounce B.C. Poirier E.Z. Passoni G. Simon-Loriere E. Cesaro T. Prot M. Stapleford K.A. Moratorio G. Sakuntabhai A. Levraud J.P. Vignuzzi M. Cell Host Microbe. 2016; 20 (this issue): 167-177Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Further, they show that IFN-β-mediated upregulation of SAT1 facilitates interconversion of polyamines to putrescine and leads to reduced polyamine levels in the cell (Figure 1). To test whether polyamine depletion is a mechanism by which the IFN response restricts virus infection, the authors utilized multiple approaches to stimulate, deplete, and replenish polyamine levels in cultured cells and in two animal models. They show that polyamines are critical for CHIKV and ZIKV. Both viral RNA replication and translation were negatively impacted by polyamine depletion and could be rescued by addition of exogenous polyamines. Given that there was minimal impact on cell viability, polyamine depletion may have clinical implications for combating viral infections. It is not surprising that polyamine depletion inhibits translation of alphaviruses and flaviviruses. It has been previously shown that polyamines affect translation at both the initiation and elongation steps (Miller-Fleming et al., 2015Miller-Fleming L. Olin-Sandoval V. Campbell K. Ralser M. J. Mol. Biol. 2015; 427: 3389-3406Crossref PubMed Scopus (394) Google Scholar). A group of cellular genes has been identified that increase their translation in the presence of polyamines. Polyamines can also affect post-translational modifications of host factors involved in translation. For example, polyamine depletion promotes changes in the phosphorylation of the translation initiation factor eIF-2α and the translation repressor protein 4E-BP, leading to inhibition of translation initiation (Park et al., 2010Park M.H. Nishimura K. Zanelli C.F. Valentini S.R. Amino Acids. 2010; 38: 491-500Crossref PubMed Scopus (237) Google Scholar). Most intriguingly, spermidine is used as a substrate for eIF-5A hypusination, a unique post-translational modification critical for eIF-5A’s activity in promoting translation of mRNAs encoding polyproline tracts (Dever et al., 2014Dever T.E. Gutierrez E. Shin B.S. Crit. Rev. Biochem. Mol. Biol. 2014; 49: 413-425Crossref PubMed Scopus (103) Google Scholar). However, several outstanding questions remain. Is SAT1 upregulated by IFN directly? While alphaviruses shut down host transcription and translation to prevent expression of ISGs (and presumably SAT1), how do flaviviruses cope with SAT1 upregulation and polyamine depletion during infection? It would be interesting to determine whether viruses have evolved mechanisms to antagonize SAT1. Furthermore, is there evidence for changes in susceptibility to viral infections in people with mutations in the polyamine pathway? Most importantly, are polyamines and their biosynthesis pathway good therapeutic targets for treating viral infections? Since Mounce and colleagues have shown that viruses are more sensitive to the effects of polyamine depletion than the host cells, there is great potential for selective blockade of viral infection with minimal cytotoxicity by inhibitors of the pathway components. On the other hand, given that the enzymes involved in the biosynthesis of polyamines are tightly regulated on multiple levels, inhibiting the activity of a single enzyme might not have significant effects on the overall cellular levels of polyamines. Although increases in polyamines and polyamine synthesis enzymes are associated with tumor growth and several drugs targeting different steps in the pathway have been developed, attempts to use them as cancer therapeutics have not been efficacious (Seiler, 2003Seiler N. Curr. Drug Targets. 2003; 4: 537-564Crossref PubMed Scopus (148) Google Scholar). It appears that polyamine metabolism is much more difficult to target than anticipated. A cocktail of drugs that targets multiple steps in the biosynthesis of polyamines or inhibitors with less specificity is likely the way forward. Further studies are needed to determine whether the available drug candidates would be effective for treating viral infections. Interferon-Induced Spermidine-Spermine Acetyltransferase and Polyamine Depletion Restrict Zika and Chikungunya VirusesMounce et al.Cell Host & MicrobeJuly 14, 2016In BriefMounce et al. demonstrate that signaling through type I interferon induces a catabolic enzyme in the host polyamine pathway, which depletes spermidine and spermine to restrict chikungunya and Zika virus replication. Polyamines were found to be crucial for viral infection in vivo, suggesting a therapeutic avenue for virus control. Full-Text PDF Open Archive" @default.
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• W2511381211 title "Polyamines: Small Molecules with a Big Role in Promoting Virus Infection" @default.
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