Human Interferon-γ mRNA Autoregulates Its Translation through a Pseudoknot that Activates the Interferon-Inducible Protein Kinase PKR
Open accessAbstract
PKR, an interferon (IFN)-inducible protein kinase activated by double-stranded RNA, inhibits translation by phosphorylating the initiation factor eIF2alpha chain. We show that human IFN-gamma mRNA uses local activation of PKR in the cell to control its own translation yield. IFN-gamma mRNA activates PKR through a pseudoknot in its 5' untranslated region. Mutations that impair pseudoknot stability reduce the ability to activate PKR and strongly increase the translation efficiency of IFN-gamma mRNA. Nonphosphorylatable mutant eIF2alpha, knockout of PKR and PKR inhibitors 2-aminopurine, transdominant-negative PKR, or vaccinia E3L correspondingly enhances translation of IFN-gamma mRNA. The potential to form the pseudoknot is phylogenetically conserved. We propose that the RNA pseudoknot acts to adjust translation of IFN-gamma mRNA to the PKR level expressed in the cell.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
IRE is a small region of a loop in a 5′UTR near the cap of a subpopulation of mRNAs involved in iron homeostasis.
“A classic example is the iron-responsive element (IRE), which is a small region of a loop in a 5′UTR near the cap of a subpopulation of mRNAs involved in iron homeostasis [10].”
From Effects of Combinations of Untranslated-Region Sequences on Translation of mRNA (2023) · cites this paper as [10]
The Results passage concerns the 5′-terminal region of IFN-γ mRNA and its activation of PKR, not an iron-responsive element. Searches for IRE, iron-responsive elements, ferritin, and iron homeostasis found no passage in our copy describing the claimed location or role of an IRE. (LLM, conf=0.72)
Experimental — accuracy not yet measuredThe IRE in mRNA encoding ferritin or ferroportin associates with IRP1 or IRP2 under low-iron conditions.
“The IRE in mRNA encoding either ferritin (iron storage protein) or ferroportin (iron transporter) associates with iron regulatory protein 1 or 2 (IRP1 or IRP2) under low-iron conditions.”
From Effects of Combinations of Untranslated-Region Sequences on Translation of mRNA (2023) · cites this paper as [10]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
No references could be resolved yet.
Research works printed but not linked: 12
- [1]1. Arad, G. ∙ Levy, R. ∙ Hillman, D. ... Superantigen antagonist protects against lethal shock and defines a new domain for T-cell activation Nat. Med. 2000; 6:414-421 Crossref Scopus (142) PubMed Google Scholar
- [2]2. Ben-Asouli, Y. ∙ Banai, Y. ∙ Hauser, H. ... Recognition of 5′-terminal TAR structure in human immunodeficiency virus-1 mRNA by eukaryotic translation initiation factor 2 Nucleic Acids Res. 2000; 28:1011-1018 Crossref Scopus (16) PubMed Google Scholar
- [3]3. Bevilacqua, P.C. ∙ Cech, T.R. Minor-groove recognition of double-stranded RNA by the double-stranded RNA-binding domain from the RNA-activated protein kinase PKR Biochemistry. 1996; 35:9983-9994 Crossref Scopus (212) PubMed Google Scholar
- [4]4. Bevilacqua, P.C. ∙ George, C.X. ∙ Samuel, C.E. ... Binding of the protein kinase PKR to RNAs with secondary structure defectsRole of the tandem A-G mismatch and noncontiguous helixes Biochemistry. 1998; 37:6303-6316 Crossref Scopus (96) PubMed Google Scholar
- [5]5. Billiau, A. Interferon-gammabiology and role in pathogenesis Adv. Immunol. 1996; 62:61-130 Crossref PubMed Google Scholar
- [6]6. Bycroft, M. ∙ Grunert, S. ∙ Murzin, A.G. ... NMR solution structure of a dsRNA binding domain from Drosophila staufen protein reveals homology to the N-terminal domain of ribosomal protein S5 EMBO J. 1995; 14:3563-3567 Crossref Scopus (232) PubMed Google Scholar
- [7]7. Chu, W.M. ∙ Ballard, R. ∙ Carpick, B.W. ... Potential Alu functionregulation of the activity of double-stranded RNA-activated kinase PKR Mol. Cell. Biol. 1998; 18:58-68 Crossref Scopus (179) PubMed Google Scholar
- [8]8. Circle, D.A. ∙ Neel, O.D. ∙ Robertson, H.D. ... Surprising specificity of PKR binding to delta agent genomic RNA RNA. 1997; 3:438-448 PubMed Google Scholar
- [9]9. Davis, S. ∙ Watson, J.C. In vitro activation of the interferon-induced, double-stranded RNA-dependent protein kinase PKR by RNA from the 3′ untranslated regions of human α-tropomyosin Proc. Natl. Acad. Sci. USA. 1996; 93:508-513 Crossref Scopus (93) PubMed Google Scholar
- [10]10. Dirks, W. ∙ Schaper, F. ∙ Hauser, H. A new hybrid promoter directs transcription at identical start points in mammalian cells and in vitro Gene. 1994; 149:389-390 Crossref Scopus (13) PubMed Google Scholar
- [11]11. Donahue, T.F. Genetic approaches to translation initiation in Saccharomyces cerevisiae Sonenberg, N. ∙ Hershey, J.W.B. ∙ Mathews, M.B. (Editors) Translational Control of Gene Expression Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2000 487–502.pp Google Scholar
- [12]12. Edery, I. ∙ Petryshyn, R. ∙ Sonenberg, N. Activation of double-stranded RNA-dependent kinase (dsI) by the TAR region of HIV-1 mRNAa novel translational control mechanism Cell. 1989; 56:303-312
Cited by
Sorted by citations
Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them
Leppek, K., Das, R., & Barna, M. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.103 · Cited by 949 · see citing works
Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation
Anderson, B. R., Muramatsu, H., Nallagatla, S. R., Bevilacqua, P. C., Sansing, L. H., Weissman, D., & Karikó, K. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq347 · Cited by 682 · see citing works
The dsRNA protein kinase PKR: Virus and cell control
García, M. A., Meurs, E. F., & Esteban, M. (2007) · Biochimie · doi:10.1016/j.biochi.2007.03.001 · Cited by 644 · see citing works
Sampath, P., Mazumder, B., Seshadri, V., & Fox, P. L. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.5.1509-1519.2003 · Cited by 130 · see citing works
Effects of Combinations of Untranslated-Region Sequences on Translation of mRNA
Kirshina, A., Vasileva, O., Kunyk, D., Seregina, K., Muslimov, A., Ivanov, R., & Reshetnikov, V. (2023) · Biomolecules · doi:10.3390/biom13111677 · Cited by 26 · see citing works
- Authors
- Ben-Asouli, Y., Banai, Y., Pel-Or, Y., Shir, A., & Kaempfer, R.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Kaempfer, Raymond
- ORCID
- Kaempfer, Raymond
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2002-01
- Volume
- 108
- Issue
- 2
- Pages
- 221-232
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1990549640
- Cited by
- 206
- References
- 0
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 6 · 2023: 9 · 2022: 5 · 2021: 6 · 2020: 7 · 2019: 12 · 2018: 4 · 2017: 10 · 2016: 8 · 2015: 4 · 2014: 8 · 2013: 13 · 2012: 4
- FWCI
- 4.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- PKR, RNA pseudoknots, eIF2α phosphorylation, translational regulation, 5' untranslated region, autoregulation, double-stranded RNA, 2-aminopurine
- MeSH terms
- Animals, Base Sequence, Cell Line, Enzyme Activation, Humans, Interferon-gamma, Molecular Sequence Data, Mutation, Nucleic Acid Conformation, Phosphorylation, Protein Binding, RNA, Messenger, Protein Biosynthesis, Eukaryotic Initiation Factor-2, Gene Expression Regulation, Enzymologic, eIF-2 Kinase, 5' Untranslated Regions
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
