Viral insulin/IGF-like peptides inhibit IGF-1 receptor signaling to enhance viral replication
The insulin/insulin growth factor (IGF) system plays a central role in regulating metabolism and growth. We identified viral insulin/IGF1-like peptides (VILPs) in Iridoviridae and investigated their role in host-virus interactions. Using grouper iridovirus (GIV) on grouper and zebrafish cells, we show that VILPs are early viral genes and are secreted during infection. VILPs activate insulin receptor (IR) and IGF-1 receptor (IGF1R) phosphorylation and stimulate the phosphatidylinositol 3-kinase (PI3K) pathway. GIV-VILP present in the supernatants of infected cells triggers dose- and time-dependent signaling through selective interaction with IGF1R. Functionally, IR inhibition suppresses GIV replication, whereas IGF1R inhibition enhances it, and IGF-1 stimulation reduces replication. During infection, GIV-VILP competes with IGF-1, attenuating IGF1R signaling and reducing proliferation. Transcriptome analysis confirms negative regulation of cell cycle pathways. Using a zebrafish infection model, we demonstrate VILP expression and IGF-1 signaling inhibition. Our findings reveal a viral mimicry mechanism that modulates host IGF-1 signaling to promote viral replication.
Authors
- Sarah K. McMenamin (ORCID: https://orcid.org/0000-0002-1154-5810)
- Jiřı́ Jiráček (ORCID: https://orcid.org/0000-0003-3848-2773)
- Marta Lubos (ORCID: https://orcid.org/0000-0002-2919-0085)
- Harish Vashisth (ORCID: https://orcid.org/0000-0002-2087-2880)
- Lev Levintov (ORCID: https://orcid.org/0000-0002-7950-9226)
- Aurélien Chuard (ORCID: https://orcid.org/0000-0001-9005-9337)
- Lenka Žáková (ORCID: https://orcid.org/0000-0001-6439-2574)
- Richard D. DiMarchi (ORCID: https://orcid.org/0000-0003-0220-4085)
- Emrah Altındiş (ORCID: https://orcid.org/0000-0001-9657-7602)
- Kalaimagal Nesarajah
- Khadija Danazumi
- Zhang Fa (ORCID: https://orcid.org/0000-0002-3749-2948)
- K. Reiners
- Rachel Ruggera
Institutions
- Boston College (US)
- University of New Hampshire (US)
- Chestnut Hill College (US)
- Indiana University Bloomington (US)
- Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-08-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116149
- Citations
- 4
- Primary Topic
- Growth Hormone and Insulin-like Growth Factors
- Type
- article
- Field-Weighted Citation Impact
- 5.18
Funders
- National Science Foundation
- Eli Lilly and Company
- Boston College
- Diabetes Research Connection
- European Commission
- Academia Sinica
- Novo Nordisk
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement
- National Institutes of Health