Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology submitted time 2016-05-12
Chen, Yongzhi
He, Liang
Peng, Yanan
Shi, Xiaodong
Cheng, Genhong
Deng, Hongyu
Chen, Yongzhi
He, Liang
Peng, Yanan
Chen, Jizheng
Chen, Xinwen
Zhong, Jin
Cheng, Genhong
Abstract： The transcription factor nuclear factor kB (NF-kappa B) is crucial for innate immune defense against viral infections, and its activation requires the ubiquitylation of upstream proteins, including the adaptor protein NEMO (NF-kappa B essential modulator). Many infectious pathogens, including hepatitis C virus (HCV), inhibit NF-kappa B signaling in host cells, which promotes pathogen survival. Frequently, HCV-infected individuals develop a chronic infection, which suggests that HCV can subvert host antiviral responses. We found that HCV infection and replication inhibited the activation of NF-kappa B by the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), which was mediated by the viral protein NS3 and, to a lesser extent, NS5B. NS3 directly interacted with linear ubiquitin chain assembly complex (LUBAC), competed with NEMO for binding to LUBAC, and inhibited the LUBAC-mediated linear ubiquitylation of NEMO and the subsequent activation of NF-kappa B. Together, our results highlight an immune evasion strategy adopted by HCV to modulate host antiviral responses and enhance virus survival and persistence.
Peer Review Status:
Awaiting Review
Subjects: Biology >> Biophysics submitted time 2016-05-11
Chen, Jizheng
Guo, Min
Tang, Hong
Chen, Xinwen
Wang, Ning
Dong, Mei
Li, Zhong
Han, Xiao
Wang, Qian
Zhao, Yang
Zhuo, Zhiyong
Zhang, Chao
Chi, Xiumei
Pan, Yu
Jiang, Jing
Niu, Junqi
Yang, Dongliang
Abstract： Class Ila histone deacetylases (HDACs), such as HDAC4, HDAC5, and HDAC7, provide critical mechanisms for regulating glucose homeostasis. Here we report that HDAC9, another class Ila HDAC, regulates hepatic gluconeogenesis via deacetylation of a Forkhead box 0 (FoxO) family transcription factor, FoxO1, together with HDAC3. Specifically, HDAC9 expression can be strongly induced upon hepatitis C virus (HCV) infection. HCV-induced HDAC9 upregulation enhances gluconeogenesis by promoting the expression of gluconeogenic genes, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, indicating a major role for HDAC9 in the development of HCV-associated exaggerated gluconeogenic responses. Moreover, HDAC9 expression levels and gluconeogenic activities were elevated in livers from HCV-infected patients and persistent HCV-infected mice, emphasizing the clinical relevance of these results. Our results suggest HDAC9 is involved in glucose metabolism, HCV-induced abnormal glucose homeostasis, and type 2 diabetes.
Peer Review Status:Awaiting Review
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