AsianScientist (Dec. 14, 2015) – A high proportion of hepatitis C-infected individuals develop chronic infections, suggesting that hepatitis C can subvert host antiviral responses. How the virus does this, previously not fully explained, is the subject of the findings of Professor Deng Hongyu and his research group from the Institute of Biophysics of the Chinese Academy of Sciences. Their results have been published in Science Signaling.
The innate immune system, the body’s first line of defence, is known to depend on the transcription factor nuclear factor κB (NF-κB). Its activation requires the ubiquitylation of upstream proteins including the adaptor protein NEMO (NF-κB essential modulator). Hepatitis C is one of many infectious pathogens that survive by inhibiting NF-κB signaling in host cells.
Normally, the inflammatory cytokine tumor necrosis factor-α (TNF-α) induces antiviral innate immune responses by stimulating NF-κB through a cascade of signaling events. However patients with chronic hepatitis C infections have increased serum amounts of TNF-α, but have ineffective immune responses due to the inhibited NF-κB activation.
The researchers hypothesized that the inhibition of TNF-α–induced NF-κB activation might be mediated by a viral protein expressed during hepatitis C infection. They used a luciferase reporter assay to screen which viral protein suppresses TNF-α–induced NF-κB activation and found that NS3 was sufficient to block NF-κB signaling in cells.
Co-immunoprecipitation and immunofluorescence staining experiments showed that NS3 directly interacted with the linear ubiquitin chain assembly complex (LUBAC). More detailed domain mapping experiments showed that NS3 is bound to the ZnF-RBZ domain of HOIP (HOIL-1L–interacting protein; also known as RNF31), which is the same domain in LUBAC that binds to NEMO.
To investigate the role of NS3 binding to HOIP, the researchers performed competitive coimmunoprecipitation experiments. They found that overexpression NS3 disrupted the interaction between HOIP and NEMO in a concentration-dependent manner. NS3 directly interacted with LUBAC, competed with NEMO for binding to LUBAC, and inhibited the LUBAC-mediated linear ubiquitylation of NEMO as well as the subsequent activation of NF-κB.
The results highlight a novel immune evasion strategy adopted by hepatitis C to modulate host antiviral responses and enhance virus survival and persistence.
The article can be found at: Chen et al. (2015) The Hepatitis C Virus Protein NS3 Suppresses TNF-α–Stimulated Activation of NF-κB by Targeting LUBAC.
———
Source: Chinese Academy of Sciences.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.
