Zika virus (ZIKV) infection in the human central nervous system (CNS) causes Guillain-Barre syndrome, cerebellum deformity, and other diseases. Astrocytes are immune response cells in the CNS and an important component of the blood-brain barrier. Consequently, any damage to astrocytes facilitates the spread of ZIKV in the CNS. Connective tissue growth factor/Nephroblastoma overexpressed gene family 1 (CCN1), an important inflammatory factor secreted by astrocytes, is reported to regulate innate immunity and viral infection. However, the mechanism by which astrocyte viral infection affects CCN1 expression remains undefined. In this study, we demonstrate that ZIKV infection up-regulates CCN1 expression in astrocytes, thus promoting intracellular viral replication. Other studies revealed that the cAMP response element (CRE) in the CCN1 promoter is activated by the ZIKV NS3 protein. The cAMP-responsive element-binding protein (CREB), a transacting factor of the CRE, is also activated by NS3 or ZIKV. Furthermore,a specific inhibitor of CREB, i.e. SGC-CBP30, reduced ZIKV-induced CCN1 up-regulation and ZIKV replication. Moreover, co-immunoprecipitation, overexpression, and knockdown studies confirmed that the interaction between NS3 and the regulatory domain of CaMKIIα could activate the CREB pathway, thus resulting in the up-regulation of CCN1 expression and enhancement of virus replication. In conclusion, the findings of our investigations on the NS3-CaMKIIα-CREB-CCN1 pathway provide a foundation for understanding the infection mechanism of ZIKV in the CNS.

We previously reported that hepatitis B virus core protein (HBc) can bind to the Enhancer I (Enh I) domain and can accumulate with transcription coactivator cAMP response element (CRE). This raises the possibility that HBc may interact with CRE/CREB and regulate CRE transcription activation. In this study, we investigated the function and mechanisms of HBc in regulating CRE transcriptional activation using the HepG2 cell line. Our results showed the following: (1) HBc expression significantly increases HBV CRE transcriptional activation; (2) phosphorylation of the serine residues in the arginine-rich domain (ARD) of HBc protein impacts the function of transcriptional activation by the CRE; (3) HBc protein significantly increases HBV CRE transcriptional activation following forskolin treatment; (4) HBc nonspecifically binds to CRE and enhances the binding of the cAMP response element-binding protein (CREB) to CRE; and (5) HBc increases the concurrent accumulation of CREB and CBP at the CRE region. HBc activates Enh I through its binding to CRE, increasing the concurrent accumulation of CREB/CBP on CRE, and thus increases CRE transcriptional activation.

Numerous studies have shown that human endogenous retrovirus W family (HERV-W) envelope gene (env) is related to various diseases but the underlying mechanism has remained poorly understood. Our previous study showed that there was abnormal expression of HERV-W env in sera of patients with schizophrenia. In this paper, we reported that overexpression of the HERV-W env elevated the levels of small conductance Ca(2+)-activated K(+) channel protein 3 (SK3) in human neuroblastoma cells. Using a luciferase reporter system and RNA interference method, we found that functional cAMP response element site was required for the expression of SK3 triggered by HERV-W env. In addition, it was also found that the SK3 channel was activated by HERV-W env. Further study indicated that cAMP response element-binding protein (CREB) was required for the activation of the SK3 channel. Thus, a novel signaling mechanism of how HERV-W env influences neuronal activity and contributes to mental illnesses such as schizophrenia was proposed.