Apoptosis repressor with caspase recruitment domain ameliorates amyloid-induced b-cell apoptosis and JNK pathway activation

Andrew T. Templin, Tanya Samarasekera, Daniel T. Meier, Meghan F. Hogan, Mahnaz Mellati, Michael T. Crow, Richard N. Kitsis, Sakeneh Zraika, Rebecca L. Hull, Steven E. Kahn

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Islet amyloid is present in more than 90% of individuals with type 2 diabetes, where it contributes to b-cell apoptosis and insufficient insulin secretion. Apoptosis repressor with caspase recruitment domain (ARC) binds and inactivates components of the intrinsic and extrinsic apoptosis pathways and was recently found to be expressed in islet b-cells. Using a human islet amyloid polypeptide transgenic mouse model of islet amyloidosis, we show ARC knockdown increases amyloid-induced b-cell apoptosis and loss, while ARC overexpression decreases amyloid-induced apoptosis, thus preserving b-cells. These effects occurred in the absence of changes in islet amyloid deposition, indicating ARC acts downstream of amyloid formation. Because islet amyloid increases c-Jun N-terminal kinase (JNK) pathway activation, we investigated whether ARC affects JNK signaling in amyloid-forming islets. We found ARC knockdown enhances JNK pathway activation, whereas ARC overexpression reduces JNK, c-Jun phosphorylation, and c-Jun target gene expression (Jun and Tnf). Immunoprecipitation of ARC from mouse islet lysates showed ARC binds JNK, suggesting interaction between JNK and ARC decreases amyloid-induced JNK phosphorylation and downstream signaling. These data indicate that ARC overexpression diminishes amyloid-induced JNK pathway activation and apoptosis in the b-cell, a strategy that may reduce b-cell loss in type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)2636-2645
Number of pages10
JournalDiabetes
Volume66
Issue number10
DOIs
StatePublished - Oct 1 2017

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Templin, A. T., Samarasekera, T., Meier, D. T., Hogan, M. F., Mellati, M., Crow, M. T., Kitsis, R. N., Zraika, S., Hull, R. L., & Kahn, S. E. (2017). Apoptosis repressor with caspase recruitment domain ameliorates amyloid-induced b-cell apoptosis and JNK pathway activation. Diabetes, 66(10), 2636-2645. https://doi.org/10.2337/db16-1352