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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
NDV inhibited IFN-β secretion through impeding CHCHD10-mediated mitochondrial fusion to promote viral proliferation
Xibing Yu1, Hexiang Jiang1, Jindou Li1
1State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China.
Abstract:
Newcastle disease virus (NDV) is an RNA virus that can promote its own replication through the inhibition of cellular mitochondrial fusion. The proteins involved in mitochondrial fusion, namely mitofusin 1 (Mfn1) and optic atrophy 1 (OPA1) are associated with interferon-beta (IFN-β) secretion during NDV infection. However, the precise mechanism by which NDV modulates the Mfn1-mediated or OPA1-mediated fusion of mitochondria, thereby impacting IFN-β, remains elusive. This study revealed that the downregulation of the mitochondrial protein known as coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) exerts a negative regulatory effect on OPA1 and Mfn1 in human lung adenocarcinoma (A549) cells during the late stage of NDV infection. This reduction in CHCHD10 expression impeded cellular mitochondrial fusion, subsequently leading to a decline in the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB), ultimately resulting in diminished secretion of IFN-β. In contrast, the overexpression of CHCHD10 alleviated infection-induced detrimental effect in mitochondrial fusion, thereby impeding viral proliferation. In summary, NDV enhances its replication by inhibiting the CHCHD10 protein, which impedes mitochondrial fusion and suppresses IFN-β production through the activation of IRF3 and NF-κB.
Insights
Newcastle disease virus (NDV) hinders mitochondrial fusion by downregulating CHCHD10 protein, which impairs interferon-beta (IFN-β) production. Restoring CHCHD10 levels impedes viral replication and boosts IFN-β secretion.
Area of Science:
- Virology
- Cell Biology
- Immunology
Background:
- Newcastle disease virus (NDV) infection impacts host cell processes, including mitochondrial dynamics.
- Mitochondrial fusion proteins mitofusin 1 (Mfn1) and optic atrophy 1 (OPA1) are linked to interferon-beta (IFN-β) secretion during NDV infection.
- The exact mechanism of NDV's modulation of mitochondrial fusion and its effect on IFN-β remains unclear.
Purpose of the Study:
- To elucidate the role of coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) in NDV-induced mitochondrial dysfunction.
- To investigate the impact of CHCHD10 on Mfn1 and OPA1 during NDV infection in human lung adenocarcinoma (A549) cells.
- To determine how CHCHD10 affects interferon regulatory factor 3 (IRF3), nuclear factor kappa B (NF-κB), and subsequent IFN-β production.
Main Methods:
- Investigated the expression levels of CHCHD10, Mfn1, and OPA1 in A549 cells during NDV infection.
- Assessed the effects of CHCHD10 downregulation and overexpression on mitochondrial fusion.
- Analyzed the activation of IRF3 and NF-κB signaling pathways.
- Measured IFN-β secretion levels.
- Evaluated the impact on viral replication.
Main Results:
- NDV infection led to the downregulation of CHCHD10 in A549 cells.
- Reduced CHCHD10 expression impaired mitochondrial fusion by negatively affecting OPA1 and Mfn1.
- This impairment suppressed the activation of IRF3 and NF-κB, resulting in diminished IFN-β secretion.
- Overexpression of CHCHD10 protected against NDV-induced mitochondrial fusion defects and reduced viral proliferation.
Conclusions:
- NDV promotes its replication by inhibiting CHCHD10, leading to impaired mitochondrial fusion.
- The inhibition of CHCHD10 suppresses IFN-β production via the IRF3 and NF-κB pathways.
- CHCHD10 plays a critical role in host antiviral defense against NDV infection by maintaining mitochondrial integrity and promoting IFN-β secretion.
