Novel modulators of p53-signaling encoded by unknown genes of emerging viruses

Alzhanova, Dina; Corcoran, Kathleen; Bailey, Aubrey; Long, Kristin M.; Taft-Benz, Sharon; Graham, Rachel L.; Broussard, Grant; Heise, Mark T.; Halfmann, Peter; Kawaoka, Yoshihiro; Baric, Ralph S.; Damania, Blossom; Dittmer, Dirk P.

doi:10.1371/journal.ppat.1009033

Cited by 12 publications

(9 citation statements)

References 90 publications

(115 reference statements)

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“…Concerning the risk in interacting with the nuclear microenvironment (host DNA), it seems to be very low. In contrast, a recently published study reported the possibility for RNA viruses-including SARS-CoV-2-to interfere with the crucial p53 "guardian of the genome" nuclear phospoprotein function (Alzhanova et al, 2021). The precise period of time after vaccination characterized by high immunogenicity and the probability of vaccinated people to be able as carriers to spread the virus still remain unknown.…”

Section: Discussionmentioning

confidence: 97%

Impact of Ribosome Activity on SARS-CoV-2 LNP – Based mRNA Vaccines

Tsiambas

Chrysovergis

Papanikolaou

et al. 2021

Front. Mol. Biosci.

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Coronavirus-related Severe Acute Respiratory Syndrome-2 (SARS-CoV-2) initially was detected in Wuhan, Hubei, China. Since early 2021, World Health Organization (WHO) has declared Coronavirus Disease 2019 (COVID-19) a pandemic due to rapidly transformed to a globally massive catastrophic viral infection. In order to confront this emergency situation, many pharmaceutical companies focused on the design and development of efficient vaccines that are considered necessary for providing a level of normalization in totally affected human social-economical activity worldwide. A variety of vaccine types are under development, validation or even some of them have already completed these stages, initially approved as conditional marketing authorisation by Food and Drug Administration (FDA), European Medicines Agency (EMA), and other national health authorities for commercial purposes (in vivo use in general population), accelerating their production and distribution process. Innovative nucleoside-modified viral messenger RNA (v-mRNA)—based vaccines encapsulated within nanoparticles—specifically lipid ones (LNPs)—are now well recognized. Although this is a promising genetic engineering topic in the field of nanopharmacogenomics or targeted nucleic vaccines, there are limited but continuously enriched in vivo data in depth of time regarding their safety, efficacy, and immune response. In the current paper we expand the limited published data in the field of ribosome machinery and SARS-CoV-2 mRNA fragment vaccines interaction by describing their functional specialization and modifications. Additionally, alterations in post-transcriptional/translational molecules and mechanisms that could potentially affect the interaction between target cells and vaccines are also presented. Understanding these mechanisms is a crucial step for the next generation v-mRNA vaccines development.

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Section: Discussionmentioning

confidence: 97%

Impact of Ribosome Activity on SARS-CoV-2 LNP – Based mRNA Vaccines

Tsiambas

Chrysovergis

Papanikolaou

et al. 2021

Front. Mol. Biosci.

View full text Add to dashboard Cite

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“…Virtually, all viruses target molecular cellular mechanisms that can control their replication, dissemination, or persistence. Among these is p53, a key gatekeeper for cell division and survival that also regulates innate immune responses ( Alzhanova et al, 2021 ). The expression and activity of key transcriptional factors, such as p53 and NF-kB are altered upon SARS-CoV-2 infection, as well as other key molecules such as the virus host cell entry mediator ACE2, member of the renin-angiotensin system RAS-pathway.…”

Section: Discussionmentioning

confidence: 99%

Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells

et al. 2022

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SARS-CoV viruses have been shown to downregulate cellular events that control antiviral defenses. They adopt several strategies to silence p53, key molecule for cell homeostasis and immune control, indicating that p53 has a central role in controlling their proliferation in the host. Specific actions are the stabilization of its inhibitor, MDM2, and the interference with its transcriptional activity. The aim of our work was to evaluate a new approach against SARS-CoV-2 by using MDM2 inhibitors to raise p53 levels and activate p53-dependent pathways, therefore leading to cell cycle inhibition. Experimental setting was performed in the alveolar basal epithelial cell line A549-hACE2, expressing high level of ACE2 receptor, to allow virus entry, as well as p53 wild-type. Cells were treated with several concentrations of Nutlin-3 or RG-7112, two known MDM2 inhibitors, for the instauration of a cell cycle block steady-state condition before and during SARS-CoV-2 infection, and for the evaluation of p53 activation and impact on virus release and related innate immune events. The results indicated an efficient cell cycle block with inhibition of the virion release and a significant inhibition of IL-6, NF-kB and IFN-λ expression. These data suggest that p53 is an efficient target for new therapies against the virus and that MDM2 inhibitors deserve to be further investigated in this field.

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“…The nucleotide sequences of ZIKV ORFs used in this study were derived from ZIKV strain H/PF/2013 (NCBI gene identifier number AHZ13508). The Heise lab (University of North Carolina, Chapel Hill, North Carolina, USA) provided their pOME plasmid-based library that permits expression of each ZIKV ORF containing a C-terminal 3XFLAG tag (35). To enable streptavidin-based affinity purification of ZIKV proteins, the ZIKV C, E, M, NS1, NS2B, and NS4A ORFs encoded in the pOME plasmids were subcloned into our modified pCAGGS expression vector (36, 37) such that they would encode a C-terminal streptavidin binding peptide (SBP) (MDEKTTGWRGGHVVEGLAGELEQLRARLEHHPQGQREP) in place of the 3XFLAG tag.…”

Section: Methodsmentioning

confidence: 99%

A global map of the Zika virus phosphoproteome reveals host-driven regulation of viral budding

Manuelyan¹,

Schmoker²,

Yount³

et al. 2021

Preprint

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Flaviviruses are enveloped, positive-strand RNA viruses that cause millions of infections in the human population annually. Although Zika virus (ZIKV) had been detected in humans as early as the 1950s, its reemergence in South America in 2015 resulted in a global health crisis. While flaviviruses encode 10 proteins that can be post-translationally modified by host enzymes, little is known regarding post-translational modifications (PTMs) of the flavivirus proteome. We used mass spectrometry to comprehensively identify host-driven PTMs on the ZIKV proteome. This approach allowed us to identify 43 PTMs across 8 ZIKV proteins, including several that are highly conserved within the Flavivirus genus. Notably, we found two phosphosites on the ZIKV envelope protein that are functionally important for viral propagation and appear to regulate viral budding. Additionally, we discovered 115 host kinases that interacted with ZIKV proteins and determined that Bosutinib, an FDA-approved tyrosine kinase inhibitor that targets ZIKV interacting host kinases, impairs ZIKV growth. Thus, we have defined a high-resolution map of host-driven PTMs on ZIKV proteins as well as cellular interacting kinases, uncovered a novel mechanism of host driven-regulation of ZIKV budding, and identified an FDA-approved inhibitor of ZIKV growth.

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Novel modulators of p53-signaling encoded by unknown genes of emerging viruses

Cited by 12 publications

References 90 publications

Impact of Ribosome Activity on SARS-CoV-2 LNP – Based mRNA Vaccines

Impact of Ribosome Activity on SARS-CoV-2 LNP – Based mRNA Vaccines

Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells

A global map of the Zika virus phosphoproteome reveals host-driven regulation of viral budding

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