Mitochondrial CMPK2 mediates immunomodulatory and antiviral activities through IFN-dependent and IFN-independent pathways

Jenn-Haung Lai; De-Wei Wu; Chien-Hsiang Wu; Li-Feng Hung; Chuan-Yueh Huang; Shuk-Man Ka; Ann Chen; Zee-Fen Chang; Ling-Jun Ho

doi:10.1016/j.isci.2021.102498

Mitochondrial CMPK2 mediates immunomodulatory and antiviral activities through IFN-dependent and IFN-independent pathways

iScience. 2021 May 3;24(6):102498. doi: 10.1016/j.isci.2021.102498. eCollection 2021 Jun 25.

Authors

Jenn-Haung Lai¹, De-Wei Wu¹, Chien-Hsiang Wu¹, Li-Feng Hung², Chuan-Yueh Huang², Shuk-Man Ka³, Ann Chen⁴, Zee-Fen Chang⁵, Ling-Jun Ho²

Affiliations

¹ Department of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Lin-Kou, Tao-Yuan, Taiwan, R.O.C.
² Institute of Cellular and System Medicine, National Health Research Institute, Zhunan, Taiwan, R.O.C.
³ Graduate Institute of Aerospace and Undersea Medicine, Department of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC.
⁴ Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
⁵ Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan.

Abstract

Mitochondria regulate the immune response after dengue virus (DENV) infection. Microarray analysis of genes identified the upregulation of mitochondrial cytidine/uridine monophosphate kinase 2 (CMPK2) by DENV infection. We used small interfering RNA-mediated knockdown (KD) and CRISPR-Cas9 knockout (KO) approaches, to investigate the role of CMPK2 in mouse and human cells. The results showed that CMPK2 was critical in DENV-induced antiviral cytokine release and mitochondrial oxidative stress and mitochondrial DNA release to the cytosol. The DENV-induced activation of Toll-like receptor (TLR)-9, inflammasome pathway, and cell migration was suppressed by CMPK2 depletion; however, viral production increased under CMPK2 deficiency. Examining mouse bone marrow-derived dendritic cells from interferon-alpha (IFN-α) receptor-KO mice and signal transducer and activator of transcription 1 (STAT1)-KO mice, we confirmed that CMPK2-mediated antiviral activity occurred in IFN-dependent and IFN-independent manners. In sum, CMPK2 is a critical factor in DENV-induced immune responses to determine innate immunity.

Keywords: Immunology; Molecular biology; Virology.