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The RNA editing enzyme ADAR1 is a
dsRNA binding protein that modifies
cellular and viral RNA sequences by adenosine deamination.
ADAR1 has been demonstrated to play important roles in embryonic erythropoiesis, viral response and RNA interference. In
human hepatitis virus infection, ADAR1 is shown to target viral
RNA and suppress viral replication through dsRNA
editing. It is not clear whether this antiviral effect of ADAR1 is
a common mechanism in response to viral infection. Here we report
a pro-viral effect of ADAR1 that enhances replication of vesicular
stomatitis virus (VSV) through a
mechanism independent of dsRNA editing. We
demonstrate that ADAR1 interacts with dsRNA-activated
protein kinase PKR, inhibits its kinase activity and suppresses eIF2a phosphorylation. Consistent with the inhibitory effect on
PKR activation, ADAR1 increases VSV infection in PKR+/+ mouse
embryonic fibroblasts; however, no significant effect was found in
PKR-/- cells. This pro-viral effect of ADAR1 requires the
N-terminal domains but does not require the deaminase
domain. These findings reveal a novel mechanism of ADAR1 that
increases host susceptibility to viral infection by inhibiting PKR
activation. 2. ADAR1 prevents stress-induced apoptosis. (unpublished data) 3. PTSD is triggered by traumatic stress-induced brain RNA
editing. Anatomically posttraumatic stress disorder (PTSD) may involve dysregulation of the amygdala, hippocampus and hypothalamic-pituitary-adrenal axis, which perform primary roles in the generation of emotion, memory consolidation, and regulating the body’s response to stress, respectively. To prevent and effectively treat PTSD, it is essential to understand the molecular regulation of these systems and to discover new and effective drug targets. Unfortunately, research on the molecular mechanisms of PTSD is still in its infancy. It is suggested by a large number of studies especially clinical research that serotonin, glutamate and adrenergic receptors play important roles in the pathophysiology of PTSD (1). Interestingly, the RNA-dependent adenosine deaminases (ADAR1 and ADAR2) are found to edit the sequences of the serotonin and glutamate receptor pre-mRNA and subsequently alter biological functions of the encoded proteins (2). Markedly, postmortem studies on brain tissues of patients with schizophrenia and major depression found distinct editing of serotonin receptor pre-mRNA in the prefrontal cortex, a brain region expressing a large number of differently edited mRNA isoforms (3). Furthermore, the most complex alterations in serotonin receptor pre-mRNA editing were found in brains of depressed suicide victims. In these brains, serotonin 5-hydroxytryptamine 2C receptors with reduced function are expressed at significantly increased levels, suggesting that the regulation of editing by synaptic serotonin is defective. These independent studies lead us to the hypothesis that pre-mRNA editing by ADAR1 and/or ADAR2 is involved in the molecular pathogenesis of PTSD. In support, ADAR1 expression is induced in stressed cells or by cytokines, while the blood cytokine level is shown to correlate with PTSD after intimate partner violence (IPV) in abused women. Last not least, ADAR2 was originally shown to involve in mental integrity and brain development. Our primary aim is to test the hypothesis that RNA editing by ADAR1 and/or ADAR2 is involved in the pathophysiological changes associated with PTSD. Positive results of this proposal will not only elucidate the molecular mechanism for the pathogenesis of PTSD, but also lead to development of new drug targets for prevention and treatment of PTSD. |
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Boston, MA
02118 | Boston, MA
02130 Fax: (857)364-5627 | Fax: (857)364-5627 jyang@bu.edu | Jinghua.yang@va.gov |
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