title: 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.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Liyun
authors.initials: L
authors.lastname: Zhao
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shoufeng
authors.initials: S
authors.lastname: Li
authors.forename: Zhenji
authors.initials: Z
authors.lastname: Gan
authors.forename: Anning
authors.initials: A
authors.lastname: Lin
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D059305:Diet, High-Fat; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D009765:Obesity / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D017393:RNA Editing / Q000187:drug effects / Q000235:genetics*; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics
chemical_list: D048055:Mitogen-Activated Protein Kinase 8; D000243:Adenosine Deaminase; D005947:Glucose