2. Academic Validation
  3. Viral hijacking of hnRNPH1 unveils a G-quadruplex-driven mechanism of stress control

Viral hijacking of hnRNPH1 unveils a G-quadruplex-driven mechanism of stress control

  • Cell Host Microbe. 2024 Sep 11;32(9):1579-1593.e8. doi: 10.1016/j.chom.2024.07.006.
Philipp Schult 1,  Beate Mareike Kümmerer 2,  Markus Hafner 3,  Katrin Paeschke 4
Affiliations

Affiliations

  • 1 Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, 53127 Bonn, Germany; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Germany.
  • 2 Institute of Virology, Medical Faculty, University of Bonn, 53127 Bonn, Germany; German Centre for Infection Research, Partner Site Bonn-Cologne, 53127 Bonn, Germany.
  • 3 RNA Molecular Biology Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA.
  • 4 Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, 53127 Bonn, Germany; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Germany. Electronic address: katrin.paeschke@ukbonn.de.
PMID: 39094585 DOI: 10.1016/j.chom.2024.07.006
Abstract

Viral genomes are enriched with G-quadruplexes (G4s), non-canonical structures formed in DNA or RNA upon assembly of four guanine stretches into stacked quartets. Because of their critical roles, G4s are potential Antiviral targets, yet their function remains largely unknown. Here, we characterize the formation and functions of a conserved G4 within the polymerase coding region of orthoflaviviruses of the Flaviviridae family. Using yellow fever virus, we determine that this G4 promotes viral replication and suppresses host stress responses via interactions with hnRNPH1, a host nuclear protein involved in RNA processing. G4 binding to hnRNPH1 causes its cytoplasmic retention with subsequent impacts on G4-containing tRNA fragments (tiRNAs) involved in stress-mediated reductions in translation. As a result, these host stress responses and associated Antiviral effects are impaired. These data reveal that the interplay between hnRNPH1 and both host and viral G4 targets controls the integrated stress response and viral replication.

Keywords

G-quadruplex; antiviral stress response; hnRNPH1; host factor; orthoflavivirus; tiRNA.

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