Abstract
Background & Aims Hepatitis C virus (HCV) is a major human viral pathogen that causes chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. In most cases, acute HCV infection becomes persistent, at least in part due to viral evasion of host innate immune response. Although HCV genomic RNA contains pathogen-associated molecular pattern (PAMP) that is able to induce host interferon responses, HCV can shut down the responses by using the viral NS3/4A protease to cleave MAVS/VISA and TRIF, two key adaptor molecules essential for the interferon signaling activation. The aim of this study was to explore a novel NS3/4A-independent mechanism HCV utilizes to evade host innate immune responses. Methods We used the interferon promoter-reporter system to screen HCV encoded proteins for their activities to suppress the interferon signaling and to determine the molecular targets of viral proteins. Co-immunoprecipitation, confocal microscopy, and siRNA-based gene silencing were used to investigate the molecular mechanism. Results We found that, in addition to NS3/4A, NS4B can suppress double-stranded RNA or RNA virus induced interferon activation. NS4B interacts with STING/MITA, an important molecule that mediates the HCV PAMP induced interferon signaling. Mechanistic studies indicated that NS4B disrupts the interactions between STING/MITA and TBK1. Conclusions In conclusion, we reported an additional mechanism for HCV evasion of host interferon responses in which viral NS4B protein targets STING/MITA to suppress the interferon signaling. Our results present important evidence for the control of interferon response by HCV, and shed more light on the molecular mechanisms underlying the persistence of HCV infection.
| Original language | English |
|---|---|
| Pages (from-to) | 52-58 |
| Number of pages | 7 |
| Journal | Journal of Hepatology |
| Volume | 59 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jul 2013 |
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Keywords
- Interferon
- Keywords Hepatitis C virus
- NS4B
- STING/MITA
- TBK-1
ASJC Scopus subject areas
- Hepatology
Cite this
Hepatitis C virus NS4B blocks the interaction of STING and TBK1 to evade host innate immunity. / Ding, Qiang; Cao, Xuezhi; Lu, Jie; Huang, Bing; Liu, Yong Jun; Kato, Nobuyuki; Shu, Hong Bing; Zhong, Jin.
In: Journal of Hepatology, Vol. 59, No. 1, 07.2013, p. 52-58.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Hepatitis C virus NS4B blocks the interaction of STING and TBK1 to evade host innate immunity
AU - Ding, Qiang
AU - Cao, Xuezhi
AU - Lu, Jie
AU - Huang, Bing
AU - Liu, Yong Jun
AU - Kato, Nobuyuki
AU - Shu, Hong Bing
AU - Zhong, Jin
PY - 2013/7
Y1 - 2013/7
N2 - Background & Aims Hepatitis C virus (HCV) is a major human viral pathogen that causes chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. In most cases, acute HCV infection becomes persistent, at least in part due to viral evasion of host innate immune response. Although HCV genomic RNA contains pathogen-associated molecular pattern (PAMP) that is able to induce host interferon responses, HCV can shut down the responses by using the viral NS3/4A protease to cleave MAVS/VISA and TRIF, two key adaptor molecules essential for the interferon signaling activation. The aim of this study was to explore a novel NS3/4A-independent mechanism HCV utilizes to evade host innate immune responses. Methods We used the interferon promoter-reporter system to screen HCV encoded proteins for their activities to suppress the interferon signaling and to determine the molecular targets of viral proteins. Co-immunoprecipitation, confocal microscopy, and siRNA-based gene silencing were used to investigate the molecular mechanism. Results We found that, in addition to NS3/4A, NS4B can suppress double-stranded RNA or RNA virus induced interferon activation. NS4B interacts with STING/MITA, an important molecule that mediates the HCV PAMP induced interferon signaling. Mechanistic studies indicated that NS4B disrupts the interactions between STING/MITA and TBK1. Conclusions In conclusion, we reported an additional mechanism for HCV evasion of host interferon responses in which viral NS4B protein targets STING/MITA to suppress the interferon signaling. Our results present important evidence for the control of interferon response by HCV, and shed more light on the molecular mechanisms underlying the persistence of HCV infection.
AB - Background & Aims Hepatitis C virus (HCV) is a major human viral pathogen that causes chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. In most cases, acute HCV infection becomes persistent, at least in part due to viral evasion of host innate immune response. Although HCV genomic RNA contains pathogen-associated molecular pattern (PAMP) that is able to induce host interferon responses, HCV can shut down the responses by using the viral NS3/4A protease to cleave MAVS/VISA and TRIF, two key adaptor molecules essential for the interferon signaling activation. The aim of this study was to explore a novel NS3/4A-independent mechanism HCV utilizes to evade host innate immune responses. Methods We used the interferon promoter-reporter system to screen HCV encoded proteins for their activities to suppress the interferon signaling and to determine the molecular targets of viral proteins. Co-immunoprecipitation, confocal microscopy, and siRNA-based gene silencing were used to investigate the molecular mechanism. Results We found that, in addition to NS3/4A, NS4B can suppress double-stranded RNA or RNA virus induced interferon activation. NS4B interacts with STING/MITA, an important molecule that mediates the HCV PAMP induced interferon signaling. Mechanistic studies indicated that NS4B disrupts the interactions between STING/MITA and TBK1. Conclusions In conclusion, we reported an additional mechanism for HCV evasion of host interferon responses in which viral NS4B protein targets STING/MITA to suppress the interferon signaling. Our results present important evidence for the control of interferon response by HCV, and shed more light on the molecular mechanisms underlying the persistence of HCV infection.
KW - Interferon
KW - Keywords Hepatitis C virus
KW - NS4B
KW - STING/MITA
KW - TBK-1
UR - http://www.scopus.com/inward/record.url?scp=84879173207&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84879173207&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2013.03.019
DO - 10.1016/j.jhep.2013.03.019
M3 - Article
C2 - 23542348
AN - SCOPUS:84879173207
VL - 59
SP - 52
EP - 58
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 1
ER -