GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation.
Hepatitis C virus (HCV) infection is a leading cause of chronic liver diseases and hepatocellular carcinoma (HCC) and Golgi protein 73 (GP73) is a serum biomarker for liver diseases and HCC. However, the mechanism underlying GP73 regulates HCV infection is largely unknown. Here, we revealed that GP7...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-04-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC5398727?pdf=render |
| _version_ | 1830404755522846720 |
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| author | Xuewu Zhang Chengliang Zhu Tianci Wang Hui Jiang Yahui Ren Qi Zhang Kailang Wu Fang Liu Yingle Liu Jianguo Wu |
| author_facet | Xuewu Zhang Chengliang Zhu Tianci Wang Hui Jiang Yahui Ren Qi Zhang Kailang Wu Fang Liu Yingle Liu Jianguo Wu |
| author_sort | Xuewu Zhang |
| collection | DOAJ |
| description | Hepatitis C virus (HCV) infection is a leading cause of chronic liver diseases and hepatocellular carcinoma (HCC) and Golgi protein 73 (GP73) is a serum biomarker for liver diseases and HCC. However, the mechanism underlying GP73 regulates HCV infection is largely unknown. Here, we revealed that GP73 acts as a novel negative regulator of host innate immunity to facilitate HCV infection. GP73 expression is activated and correlated with interferon-beta (IFN-β) production during HCV infection in patients' serum, primary human hepatocytes (PHHs) and human hepatoma cells through mitochondrial antiviral signaling protein (MAVS), TNF receptor-associated factor 6 (TRAF6) and mitogen-activated protein kinase kinase/extracellular regulated protein kinase (MEK/ERK) pathway. Detailed studies revealed that HCV infection activates MAVS that in turn recruits TRAF6 via TRAF-interacting-motifs (TIMs), and TRAF6 subsequently directly recruits GP73 to MAVS via coiled-coil domain. After binding with MAVS and TRAF6, GP73 promotes MAVS and TRAF6 degradation through proteasome-dependent pathway. Moreover, GP73 attenuates IFN-β promoter, IFN-stimulated response element (ISRE) and nuclear factor κB (NF-κB) promoter and down-regulates IFN-β, IFN-λ1, interleukin-6 (IL-6) and IFN-stimulated gene 56 (ISG56), leading to the repression of host innate immunity. Finally, knock-down of GP73 down-regulates HCV infection and replication in Huh7-MAVSR cells and primary human hepatocytes (PHHs), but such repression is rescued by GP73m4 (a mutant GP73 resists to GP73-shRNA#4) in Huh7-MAVSR cells, suggesting that GP73 facilitates HCV infection. Taken together, we demonstrated that GP73 acts as a negative regulator of innate immunity to facilitate HCV infection by interacting with MAVS/TRAF6 and promoting MAVS/TRAF6 degradation. This study provides new insights into the mechanism of HCV infection and pathogenesis, and suggests that GP73 is a new potential antiviral target in the prevention and treatment of HCV associated diseases. |
| first_indexed | 2024-12-20T17:31:48Z |
| format | Article |
| id | doaj.art-b5a640908626463f9dfa1c985b6ade7c |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-20T17:31:48Z |
| publishDate | 2017-04-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Pathogens |
| spelling | doaj.art-b5a640908626463f9dfa1c985b6ade7c2022-12-21T19:31:22ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742017-04-01134e100632110.1371/journal.ppat.1006321GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation.Xuewu ZhangChengliang ZhuTianci WangHui JiangYahui RenQi ZhangKailang WuFang LiuYingle LiuJianguo WuHepatitis C virus (HCV) infection is a leading cause of chronic liver diseases and hepatocellular carcinoma (HCC) and Golgi protein 73 (GP73) is a serum biomarker for liver diseases and HCC. However, the mechanism underlying GP73 regulates HCV infection is largely unknown. Here, we revealed that GP73 acts as a novel negative regulator of host innate immunity to facilitate HCV infection. GP73 expression is activated and correlated with interferon-beta (IFN-β) production during HCV infection in patients' serum, primary human hepatocytes (PHHs) and human hepatoma cells through mitochondrial antiviral signaling protein (MAVS), TNF receptor-associated factor 6 (TRAF6) and mitogen-activated protein kinase kinase/extracellular regulated protein kinase (MEK/ERK) pathway. Detailed studies revealed that HCV infection activates MAVS that in turn recruits TRAF6 via TRAF-interacting-motifs (TIMs), and TRAF6 subsequently directly recruits GP73 to MAVS via coiled-coil domain. After binding with MAVS and TRAF6, GP73 promotes MAVS and TRAF6 degradation through proteasome-dependent pathway. Moreover, GP73 attenuates IFN-β promoter, IFN-stimulated response element (ISRE) and nuclear factor κB (NF-κB) promoter and down-regulates IFN-β, IFN-λ1, interleukin-6 (IL-6) and IFN-stimulated gene 56 (ISG56), leading to the repression of host innate immunity. Finally, knock-down of GP73 down-regulates HCV infection and replication in Huh7-MAVSR cells and primary human hepatocytes (PHHs), but such repression is rescued by GP73m4 (a mutant GP73 resists to GP73-shRNA#4) in Huh7-MAVSR cells, suggesting that GP73 facilitates HCV infection. Taken together, we demonstrated that GP73 acts as a negative regulator of innate immunity to facilitate HCV infection by interacting with MAVS/TRAF6 and promoting MAVS/TRAF6 degradation. This study provides new insights into the mechanism of HCV infection and pathogenesis, and suggests that GP73 is a new potential antiviral target in the prevention and treatment of HCV associated diseases.http://europepmc.org/articles/PMC5398727?pdf=render |
| spellingShingle | Xuewu Zhang Chengliang Zhu Tianci Wang Hui Jiang Yahui Ren Qi Zhang Kailang Wu Fang Liu Yingle Liu Jianguo Wu GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation. PLoS Pathogens |
| title | GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation. |
| title_full | GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation. |
| title_fullStr | GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation. |
| title_full_unstemmed | GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation. |
| title_short | GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation. |
| title_sort | gp73 represses host innate immune response to promote virus replication by facilitating mavs and traf6 degradation |
| url | http://europepmc.org/articles/PMC5398727?pdf=render |
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