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 nonstructural 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 with 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 mitochondrial antiviral signaling protein (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. Conclusion: 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.
| Original language | English |
|---|---|
| Journal | Hepatology |
| DOIs | |
| Publication status | E-pub ahead of print - Aug 2 2018 |
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ASJC Scopus subject areas
- Hepatology
Cite this
Negative Regulation of Mitochondrial Antiviral Signaling Protein–Mediated Antiviral Signaling by the Mitochondrial Protein LRPPRC During Hepatitis C Virus Infection. / Refolo, Giulia; Ciccosanti, Fabiola; Di Rienzo, Martina; Basulto Perdomo, Ariel; Romani, Marta; Alonzi, Tonino; Tripodi, Marco; Ippolito, Giuseppe; Piacentini, Mauro; Fimia, Gian Maria.
In: Hepatology, 02.08.2018.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Negative Regulation of Mitochondrial Antiviral Signaling Protein–Mediated Antiviral Signaling by the Mitochondrial Protein LRPPRC During Hepatitis C Virus Infection
AU - Refolo, Giulia
AU - Ciccosanti, Fabiola
AU - Di Rienzo, Martina
AU - Basulto Perdomo, Ariel
AU - Romani, Marta
AU - Alonzi, Tonino
AU - Tripodi, Marco
AU - Ippolito, Giuseppe
AU - Piacentini, Mauro
AU - Fimia, Gian Maria
PY - 2018/8/2
Y1 - 2018/8/2
N2 - Hepatitis C virus (HCV) is highly efficient in establishing a chronic infection, having evolved multiple strategies to suppress the host antiviral responses. The HCV nonstructural 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 with 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 mitochondrial antiviral signaling protein (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. Conclusion: 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.
AB - Hepatitis C virus (HCV) is highly efficient in establishing a chronic infection, having evolved multiple strategies to suppress the host antiviral responses. The HCV nonstructural 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 with 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 mitochondrial antiviral signaling protein (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. Conclusion: 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.
UR - http://www.scopus.com/inward/record.url?scp=85058693863&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058693863&partnerID=8YFLogxK
U2 - 10.1002/hep.30149
DO - 10.1002/hep.30149
M3 - Article
AN - SCOPUS:85058693863
JO - Hepatology
JF - Hepatology
SN - 0270-9139
ER -