Abstract
Sec8, an exocyst complex subunit, is pivotal in facilitating the docking of exocytic vesicles to fusion sites on the plasma membrane. However, its involvement in the antiviral innate immune response and virus replication remains unclear. In this study, Sec8 is identified as a novel positive regulator of RIG-I, enhancing the IFN-I signaling response against RNA viruses both in vivo and in vitro. Additionally, Sec8 stabilizes RIG-I by inhibiting its ubiquitination and subsequent proteasome-mediated degradation. Mechanistically, STUB1 degrades RIG-I via K48-linked ubiquitination at Lys190, while Sec8 suppresses STUB1 mRNA by reducing the expression of p53 and competes with STUB1 for binding to RIG-I’s CARD domain, thereby preventing STUB1-mediated RIG-I degradation. Importantly, Sec8-deficient mice were more susceptible to RNA virus infection compared to wild-type mice. These findings elucidate a mechanism that Sec8 positively regulates RIG-I in the antiviral innate immune response, offering insights for developing novel therapeutic strategies and targeted antiviral medications.
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Acknowledgements
This research received partial funding from the National Natural Science Fund of China (Grants 32202772 and 32573338), the Jinan Innovation Team (202228060), the Shandong Provincial Natural Science Foundation (ZR2024MC149), and the Jinan Research Pioneer Workshop (202333059).
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HBH and HMW conceived the study; LW designed and conducted the experiments, analyzed the data, and drafted the initial manuscript; RJ and XXW carried out the majority of the immunoblotting and qPCR experiments; XYL performed the dual-luciferase reporter experiments; DCH explored and constructed the recombinant plasmids of Sec8; WQM and PLH contributed to editing and revising the draft. All authors reviewed and approved the final version of the manuscript.
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6–8 weeks old C57BL/6 (B6) mice, both Sec8fl/fl and Lyz2-Cre Sec8fl/fl mice were used in the experiments. All animal experiments were conducted strictly with the Regulations on the Administration of Experimental Animal Affairs of the People’s Republic of China, established by the State Council on November 1, 1988, as approved by the Institutional Animal Care and Use Committee (IACUC) of Shandong Normal University (Ethics approval number: AEECSDNU2023070). All experiments were conducted with the informed consent of all participants.
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Wang, L., Ma, W., Hou, P. et al. Sec8: a novel positive regulator of RIG-I in anti-RNA viral defense. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08414-9
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DOI: https://doi.org/10.1038/s41419-026-08414-9
