Upstream ORFs as Regulators of Viral Replication
- 1Chemistry Department, Lomonosov Moscow State University, 119992 Moscow, Russia
- 2Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- 3Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119992 Moscow, Russia
Abstract
Upstream open reading frames (uORFs) are widespread regulatory elements located in the 5′-untranslated regions of eukaryotic and viral mRNAs. Once considered rare exceptions to the canonical scanning model, uORFs are now recognized as actively translated features present in approximately half of human transcripts, frequently initiating at non-canonical start codons. In eukaryotes, uORFs fine-tune protein synthesis in response to cellular stress by modulating ribosome reinitiation, as exemplified by the stress-dependent regulation of ATF4 and GCN4. In viral genomes, uORFs serve as compact, evolutionarily conserved modules that optimize protein stoichiometry, coordinate expression with the host cell state, and support persistent infection across diverse viral families through cis-regulation of translation. Beyond this, uORF-encoded peptides (uPeptides) can possess independent biological activities, influencing virulence, tissue tropism, and immune modulation. In this review, we systematize the available data on the dual functionality of uORFs as cis-regulatory elements of translation and as sources of bioactive uPeptides in viruses. Deciphering the full spectrum of uORF-mediated mechanisms may reveal novel layers of viral replication control and uncover potential targets for antiviral development, although, as discussed here, the available evidence for such applications is still largely limited to proof-of-principle mutagenesis.
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BibTeX
@article{agapkina2026upstream,
title = {{Upstream ORFs as Regulators of Viral Replication}},
author = {Yulia Agapkina and Anna Mashkovskaia and Sofia Shekhtman and Sergey Korolev and Tatiana Kikhai and Andrey Anisenko and Marina Gottikh},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219821},
url = {https://www.mdpi.com/1422-0067/27/21/9821},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Upstream ORFs as Regulators of Viral Replication
AU - Yulia Agapkina
AU - Anna Mashkovskaia
AU - Sofia Shekhtman
AU - Sergey Korolev
AU - Tatiana Kikhai
AU - Andrey Anisenko
AU - Marina Gottikh
PY - 2026
DA - 2026/11/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219821
UR - https://www.mdpi.com/1422-0067/27/21/9821
AB - Upstream open reading frames (uORFs) are widespread regulatory elements located in the 5′-untranslated regions of eukaryotic and viral mRNAs. Once considered rare exceptions to the canonical scanning model, uORFs are now recognized as actively translated features present in approximately half of human transcripts, frequently initiating at non-canonical start codons. In eukaryotes, uORFs fine-tune protein synthesis in response to cellular stress by modulating ribosome reinitiation, as exemplified by the stress-dependent regulation of ATF4 and GCN4. In viral genomes, uORFs serve as compact, evolutionarily conserved modules that optimize protein stoichiometry, coordinate expression with the host cell state, and support persistent infection across diverse viral families through cis-regulation of translation. Beyond this, uORF-encoded peptides (uPeptides) can possess independent biological activities, influencing virulence, tissue tropism, and immune modulation. In this review, we systematize the available data on the dual functionality of uORFs as cis-regulatory elements of translation and as sources of bioactive uPeptides in viruses. Deciphering the full spectrum of uORF-mediated mechanisms may reveal novel layers of viral replication control and uncover potential targets for antiviral development, although, as discussed here, the available evidence for such applications is still largely limited to proof-of-principle mutagenesis.
SN - 1422-0067
ER -