Negative Regulation of Mitochondrial Antiviral Signaling Protein–Mediated Antiviral Signaling by the Mitochondrial Protein LRPPRC During Hepatitis C Virus Infection

Abstract

Hepatitis C virus (HCV) is highly efficient in establishing a chronic infection, having evolved multiple strategies to suppress the host antiviral responses. The HCV non-structural 5A (NS5A) protein, in addition to its role in viral replication and assembly, has long been known to hamper the interferon (IFN) response. However, the mechanism of this inhibitory activity of NS5A remains partly characterized. In a functional proteomic screening carried out in HCV replicon cells, we identified the mitochondrial protein LRPPRC as an NS5A binding factor. Notably, we found that downregulation of LRPPRC expression results in a significant inhibition of HCV infection, which is associated to an increased activation of the IFN response. Moreover, we showed that LRPPRC acts as a negative regulator of the mitochondrial-mediated antiviral immunity, by interacting with MAVS and inhibiting its association with TRAF3 and TRAF6. Finally, we demonstrated that NS5A is able to interfere with MAVS activity in a LRPPRC-dependent manner. Overall, our results indicate that NS5A contributes to the inhibition of innate immune pathways during HCV infection by exploiting the ability of LRPPRC to inhibit MAVS-regulated antiviral signaling. This article is protected by copyright. All rights reserved.

Mitochondrial Interactome: A Focus on Antiviral Signaling Pathways

“…NS5A coIP was carried out using n-dodecyl β-D-maltoside as a detergent to preserve the integrity of mitochondrial membrane complexes. We found that HCV NS5A interacts with the mitochondrial protein LRPPRC and represses the antiviral response by promoting LRPPRC association with MAVS, which results in a reduced association of MAVS with TRAF proteins (Refolo et al, 2019).…”

“…LRPPRC, a protein known to regulate mitochondrial RNA stability, has been characterized as a negative regulator of the mitochondrial-mediated antiviral immunity during HCV infection. In particular, LRPPRC interacts with MAVS and inhibits its signaling by preventing the association with TRAF3 and TRAF6 (Refolo et al, 2019).…”

Humoral responses to the measles, mumps and rubella vaccine are impaired in Leigh Syndrome French Canadian patients

“…In the context of patients carrying a mutation in LRPPRC, these differences may further contribute to the distinct outcomes of the immune responses. As documented for hepatitis C, different viral proteins could also influence the efficacy of the immune response in LSFC patients by directly interacting with LRPPRC [42]. Alternatively, if not for the differences in the virus themselves, the reason for the lower antibody seropositivity to mumps and rubella could be due to differences in patient viral exposure.…”

Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development

“…Accordingly, HCV suppresses IFN signaling via autophagy, for example, by depleting TRAF6 through autophagic degradation, as mentioned above (Chan et al, 2016). Recently, NS5A was found to suppress both IFN signaling and autophagy by interacting with the mitochondrial autophagy inhibitor LRPPRC (Refolo et al, 2019). Conversely, knockdown of BECLIN 1, or ATG7 or ATG5, and treatment with autophagy inhibitors, such as chloroquine or Bafilomycin A, enhance the expression of type I interferon (IFN) and interferon-stimulated genes (ISGs) in HCVinfected cells (Ke and Chen, 2011;Shrivastava et al, 2011).…”