2. Academic Validation
  3. USP18 enhances dengue virus replication by regulating mitochondrial DNA release

USP18 enhances dengue virus replication by regulating mitochondrial DNA release

  • Sci Rep. 2023 Nov 17;13(1):20126. doi: 10.1038/s41598-023-47584-w.
Jenn-Haung Lai 1,  De-Wei Wu 2,  Chien-Hsiang Wu 2,  Li-Feng Hung 3,  Chuan-Yueh Huang 3,  Shuk-Man Ka 4,  Ann Chen 5,  Ling-Jun Ho 6
Affiliations

Affiliations

  • 1 Department of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital, Lin-Kou, Tao-Yuan, Taiwan, ROC. laiandho@gmail.com.
  • 2 Department of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital, Lin-Kou, Tao-Yuan, Taiwan, ROC.
  • 3 Institute of Cellular and System Medicine, National Health Research Institute, Zhunan, Taiwan, ROC.
  • 4 Graduate Institute of Aerospace and Undersea Medicine, Department of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC.
  • 5 Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
  • 6 Institute of Cellular and System Medicine, National Health Research Institute, Zhunan, Taiwan, ROC. lingjunho@nhri.org.tw.
PMID: 37978268 DOI: 10.1038/s41598-023-47584-w
Abstract

Dengue virus (DENV) Infection remains a challenging health threat worldwide. Ubiquitin-Specific Protease 18 (USP18), which preserves the anti-interferon (IFN) effect, is an ideal target through which DENV mediates its own immune evasion. However, much of the function and mechanism of USP18 in regulating DENV replication remains incompletely understood. In addition, whether USP18 regulates DENV replication merely by causing IFN hyporesponsiveness is not clear. In the present study, by using several different approaches to block IFN signaling, including IFN neutralizing Antibodies (Abs), anti-IFN receptor Abs, Janus kinase inhibitors and IFN alpha and beta receptor subunit 1 (IFNAR1)knockout cells, we showed that USP18 may regulate DENV replication in IFN-associated and IFN-unassociated manners. Localized in mitochondria, USP18 regulated the release of mitochondrial DNA (mtDNA) to the cytosol to affect viral replication, and mechanisms such as mitochondrial Reactive Oxygen Species (mtROS) production, changes in mitochondrial membrane potential, mobilization of calcium into mitochondria, 8-oxoguanine DNA glycosylase 1 (OGG1) expression, oxidation and fragmentation of mtDNA, and opening of the mitochondrial permeability transition pore (mPTP) were involved in USP18-regulated mtDNA release to the cytosol. We therefore identify mitochondrial machineries that are regulated by USP18 to affect DENV replication and its association with IFN effects.

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