Zebrafish USP14 Suppresses RIG-I-Mediated Innate Antiviral Immunity via Targeted Deubiquitination to Facilitate SVCV Replication.

Authors

Hongying Zhang, Jihuan Hu, Chuxin Wu, Zijia Yin, Xiaowen Xu, Chengyu Hu, Dongming Li, Zeyin Jiang

Published in

Fish & shellfish immunology. Pages 111658. Aug 17, 2026. Epub Aug 17, 2026.

Abstract

Innate immunity serves as the host's primary defense against viral infection. Aberrant immune activation can trigger tissue damage and autoinflammatory disorders, which requires precise negative regulation to sustain immune homeostasis. RIG-I is a vital pattern recognition receptor that governs antiviral innate immune responses, and its function is tightly controlled by post-translational modifications. Ubiquitination directly modulates RIG-I activity, yet the regulatory mechanism underlying RIG-I inactivation in teleost fish remains poorly understood. Ubiquitin specific peptidase 14 (USP14) is an important deubiquitinating enzyme that regulates proteasome function and eliminates intracellular toxic proteins. In this study, we systematically explored the regulatory role and molecular mechanism of zebrafish USP14 in RIG-I-mediated antiviral innate immunity. Our results demonstrated that spring viremia of carp virus (SVCV) stimulation markedly upregulated USP14 expression in zebrafish. USP14 overexpression decreased the phosphorylation levels of TBK1 and IRF3, thereby repressing type I interferon (IFN1) production. USP14 is primarily localized to mitochondria, and partially localized to the Golgi apparatus and the endoplasmic reticulum. In addition, protein interaction assays and molecular docking verified the direct binding between USP14 and RIG-I. Mechanistically, USP14 removes K63-linked and K29-linked ubiquitin chains from RIG-I, and this deubiquitination suppresses RIG-I-mediated immune activation. Functional validation showed that USP14 overexpression enhances SVCV replication and induces cell death. Conversely, USP14 knockdown or treatment with its specific inhibitor IU1 abolishes these pro-viral effects. In conclusion, zebrafish USP14 functions as a deubiquitinase that interacts with RIG-I and removes its K63-linked ubiquitination. This modification inhibits RIG-I-dependent IFN signaling, impairs host antiviral immunity, and consequently promotes SVCV proliferation.

PMID:
42607976
Bibliographic data and abstract were imported from PubMed on 18 Aug 2026.

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