ISG15-USP18 signaling restrains viperin-dependent metabolic antiviral restriction

Kahler, N. L.; Rezene, S.; Scholte, F. E.; Ambikan, A. T.; Saccon, E.; Monteil, V.; Naval, P.; Macmillan, R.; Frick, S.; Noren, J.; Lourda, M.; Mirazimi, A.; Bryceson, Y. T.; Lira-Junior, R.; Prasad, V.; Vegvari, A.; Neogi, U.; Bamford, C.; Hofer, A.; Bergeron, E.; Purhonen, J.; Gupta, S.

doi:10.64898/2026.03.13.711570

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bioRxiv · 10.64898/2026.03.13.711570

ISG15-USP18 signaling restrains viperin-dependent metabolic antiviral restriction

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Abstract

Type I interferon (IFN-I) responses are tightly regulated to balance antiviral defense with cellular homeostasis. In humans, interferon-stimulated gene 15 (ISG15) functions as a critical negative regulator of IFN-I signaling by stabilizing the IFN negative regulator USP18, yet the functional consequences of ISG15 deficiency remain elusive. Here, we show that the loss of ISG15 exaggerates the JAK-STAT activation and, downstream, amplifies multiple ISGs including the nucleotide-modifying enzyme RSAD2 (viperin). Our quantitative proteomics, genetic reconstitution, and signaling analyses establish that defective USP18 stabilization skews the IFN response towards viperin expression. This amplified ISG network promotes viperin-catalyzed accumulation of the antiviral nucleotide analog ddhCTP, resulting in enhanced inhibition of viral RNA synthesis and the replication of Crimean-Congo hemorrhagic fever virus and SARS-CoV-2. Together, these findings demonstrate an ISG15-USP18-viperin axis that can be targeted to boost the metabolic antiviral restriction.

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Kahler, N. L., Rezene, S., Scholte, F. E., Ambikan, A. T., Saccon, E., Monteil, V., Naval, P., Macmillan, R., Frick, S., Noren, J., Lourda, M., Mirazimi, A., Bryceson, Y. T., Lira-Junior, R., Prasad, V., Vegvari, A., Neogi, U., Bamford, C., Hofer, A., Bergeron, E., Purhonen, J., Gupta, S.. 2026-03-14. ISG15-USP18 signaling restrains viperin-dependent metabolic antiviral restriction. https://doi.org/10.64898/2026.03.13.711570

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