c-Jun Amino-Terminal Kinase-1 Mediates Glucose-Responsive Upregulation of the RNA Editing Enzyme ADAR2 in Pancreatic Beta-Cells

Abstract

A-to-I RNA editing catalyzed by the two main members of the adenosine deaminase acting on RNA (ADAR) family, ADAR1 and ADAR2, represents a RNA-based recoding mechanism implicated in a variety of cellular processes. Previously we have demonstrated that the expression of ADAR2 in pancreatic islet β-cells is responsive to the metabolic cues and ADAR2 deficiency affects regulated cellular exocytosis. To investigate the molecular mechanism by which ADAR2 is metabolically regulated, we found that in cultured β-cells and primary islets, the stress-activated protein kinase JNK1 mediates the upregulation of ADAR2 in response to changes of the nutritional state. In parallel with glucose induction of ADAR2 expression, JNK phosphorylation was concurrently increased in insulin-secreting INS-1 β-cells. Pharmacological inhibition of JNKs or siRNA knockdown of the expression of JNK1 prominently suppressed glucose-augmented ADAR2 expression, resulting in decreased efficiency of ADAR2 auto-editing. Consistently, the mRNA expression of Adar2 was selectively reduced in the islets from JNK1 null mice in comparison with that of wild-type littermates or JNK2 null mice, and ablation of JNK1 diminished high-fat diet-induced Adar2 expression in the islets from JNK1 null mice. Furthermore, promoter analysis of the mouse Adar2 gene identified a glucose-responsive region and revealed the transcription factor c-Jun as a driver of Adar2 transcription. Taken together, these results demonstrate that JNK1 serves as a crucial component in mediating glucose-responsive upregulation of ADAR2 expression in pancreatic β-cells. Thus, the JNK1 pathway may be functionally linked to the nutrient-sensing actions of ADAR2-mediated RNA editing in professional secretory cells.

Reciprocal regulation of A-to-I RNA editing and the vertebrate nervous system

“…One example is the potential ADAR2 regulation by CA1-specific changes of cAMP-response element-binding protein (CREB) activity that occur following transient ischemic insults (Peng et al, 2006; Kitagawa, 2007). Consistent with these suggestions, the ADAR2 promoter contains a CREB/AP-1 binding site, which incidentally has shown necessary for ADAR2 regulation in glucose-responsive pancreatic cells via the stress-activated protein kinase JNK1 pathway (Yang et al, 2012). Furthermore, a link between calcium signaling via L-type voltage-gated calcium channels and activation of nuclear CREB might be key to understanding activity-dependent changes in ADAR2 expression (Wheeler et al, 2008; Balik et al, 2013).…”

Enhanced long term potentiation and decreased AMPA receptor desensitization in the acute period following a single kainate induced early life seizure

“…It is unlikely that this site is 100% edited at the developmental time point examined (Lomeli et al, 1994; Balik et al, 2012); however, whether or not a 40% increase in the expression of ADAR2 can account for changes in the editing of the AMPAR has not been shown. ADAR2 expression is regulated by multiple mechanisms (Rueter et al, 1999; Marcucci et al, 2011; Balik et al, 2013; Yang et al, 2012); however, whether these mechanisms can account for increased ADAR2 expression in KA-ELS CA1 has yet to be clarified. ADAR2 also has many targets beyond AMPARs (Keegan et al, 2004), many of which have altered editing in response to neuronal activity (Sanjana et al, 2012), and unexplored roles in plasticity.…”

A-to-I editing of coding and non-coding RNAs by ADARs

“…1a). ADAR2 expression is positively regulated by the transcription activator CREB (cyclic adenosine monophosphate response element-binding protein) in the brain 60 , and by c-Jun N-terminal kinase 1 (JNK1; also known as MAPK8) in pancreatic β-cells 61 . Interestingly, CREB also suppresses transcription from the ADAR1p110 promoter in metastatic melanomas 62 .…”