Early growth response-1 facilitates enterovirus 71 replication by direct binding to the viral genome RNA.
Enterovirus 71 (EV71) infections can cause hand, foot and mouth disease (HFMD), meningoencephalitis, neonatal sepsis, and even fatal encephalitis in children. Unfortunately, there is currently no effective treatment for EV71 infection due to the lack of understanding of viral replication and infection; and viral infections have emerged as an imperative global hazard. Thus, it is extremely important to understand the mechanism of EV71 replication in order to prevent and control the diseases associated with EV71 infections. Early growth response-1 (EGR1) is a multifunctional transcription factor that regulates diverse biological functions, including inflammation, apoptosis, differentiation, tumorigenesis, and even viral infection. Here, we provide new insight into the role of EV71 infection in regulating EGR1 production; and reveal a novel mechanism by which EGR1 facilitates EV71 replication. We demonstrate that EV71 activates EGR1 expression during infection by stimulating the protein kinase A/protein kinase Cɛ/phosphoinositide 3-kinase/Akt (PKA/PKCɛ/PI3K/Akt) cascade. We further reveal that EV71-activated EGR1, in turn, regulates the internal ribosomal entry site (IRES) of EV71 to enhance viral replication. In addition, EGR1 facilitates EV71 replication by binding directly to stem-loops I and IV of EV71 5'-untranslated region (5'UTR) with its first two zinc fingers. Moreover, EGR1 protein co-localizes with EV71 RNA in the cytoplasm of infected cells to facilitate viral replication. Our results reveal an important new role of EGR1 in viral infection, provide new insight into the novel mechanism underlying the regulation of EV71 replication, and suggest a potential application of EGR1 in the control of EV71 infection.
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
Yu
Y
Song
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
Xin
X
Cheng
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
Xiaoxia
X
Yang
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
Rong
R
Zhao
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
Peili
P
Wang
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
Yang
Y
Han
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
Zhen
Z
Luo
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
Yanhua
Y
Cao
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
Chengliang
C
Zhu
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
Ying
Y
Xiong
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
Yingle
Y
Liu
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
Kailang
K
Wu
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address: jwu@whu.edu.cn.
Jianguo
J
Wu
D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000378:metabolism / Q000502:physiology*; D029821:Enterovirus A, Human / Q000502:physiology*; D004769:Enterovirus Infections / Q000235:genetics / Q000821:virology; D005786:Gene Expression Regulation; D016679:Genome, Viral; D057809:HEK293 Cells; D006801:Humans; D011485:Protein Binding; D012367:RNA, Viral / Q000378:metabolism*; D014779:Virus Replication / Q000235:genetics
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D012367:RNA, Viral
5′-Untranslated region; Early growth response-1; Enterovirus 71; RNA–protein interaction; Viral replication