The 4EHP/GIGYF2 translation repressor complex is co-opted by the vaccinia virus K3L protein as a potential mechanism of immunoevasion
Poxviruses have evolved robust immunoevasion strategies to facilitate replication in the cytosol. We previously reported that like several RNA viruses, vaccinia virus replication is impaired in the absence of the host cap-binding translation repressor protein 4EHP (eIF4E2), implicating the latter in host antiviral defense regulation and immunosuppression. Here, we show that the vaccinia virus-encoded K3L protein interacts with 4EHP via its obligatory binding partner GIGYF2 to increase the stability of the 4EHP/GIGYF2 complex. Consequently, K3L bolsters 4EHP/GIGYF2-mediated mRNA translation repression. Thus, we demonstrate that a 4EHP/GIGYF2-mediated mechanism is exploited by and conserved among RNA and DNA viruses as a potential immunoevasion strategy. Our findings document a 4EHP/GIGYF2-dependent stringent regulation of infection by poxviruses, a clinically important family of viruses that are employed as vaccine vectors and in oncolytic viral therapy.
Authors
- Arkady Khoutorsky (ORCID: https://orcid.org/0000-0003-3846-8728)
- Michel L. Tremblay (ORCID: https://orcid.org/0000-0002-0281-541X)
- Stefan Düsterhöft (ORCID: https://orcid.org/0000-0002-6926-136X)
- Niaz Mahmood (ORCID: https://orcid.org/0000-0003-4018-5516)
- Nahum Sonenberg (ORCID: https://orcid.org/0000-0002-4707-8759)
- Adrian Pelin (ORCID: https://orcid.org/0000-0002-7454-1753)
- Nevan J. Krogan (ORCID: https://orcid.org/0000-0003-4902-337X)
- Huy‐Dung Hoang (ORCID: https://orcid.org/0000-0001-8793-1673)
- Jean‐François Trempe (ORCID: https://orcid.org/0000-0002-6543-3371)
- Reese Jalal Ladak
- Tommy Alain (ORCID: https://orcid.org/0000-0002-0396-9138)
- Albert M. Berghuis (ORCID: https://orcid.org/0000-0002-2663-025X)
- Seyed Mehdi Jafarnejad (ORCID: https://orcid.org/0000-0002-5129-7081)
- Mohamed Moustafa-Kamal (ORCID: https://orcid.org/0000-0002-3937-323X)
- Tom McGirr
- Chenyue Wu (ORCID: https://orcid.org/0000-0002-5059-1828)
- Chelsea Abboud
- Andia Moshari
- Jose G. Teodoro
- Haotian Zhuang
- Patric Harris Snell
- Jonathan Blanchet
- Jung-Hyun Choi
Institutions
- Queen's University Belfast (GB)
- Gladstone Institutes (US)
- University of Ottawa (CA)
- Chungbuk National University (KR)
- University of California, San Francisco (US)
- Children's Hospital of Eastern Ontario (CA)
- Edwards (United Kingdom) (GB)
- Quantitative BioSciences (US)
- Westfälische Hochschule (DE)
- McGill University (CA)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-09-08
- DOI
- https://doi.org/10.1073/pnas.2618090123
- Primary Topic
- Poxvirus research and outbreaks
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Research Foundation of Korea
- Terry Fox Research Institute
- Canadian Institutes of Health Research
- Biotechnology and Biological Sciences Research Council