Journal
UPSALA JOURNAL OF MEDICAL SCIENCES
Volume 121, Issue 2, Pages 133-139Publisher
TAYLOR & FRANCIS LTD
DOI: 10.3109/03009734.2015.1135217
Keywords
Apoptosis; c-Jun N-terminal kinase; cytokines; ER stress; IRE1 alpha; type 1 diabetes
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Funding
- Juvenile Diabetes Research Foundation International (JDRF) [17-2013-515]
- Actions de Recherche Concertee de la Communaute Francaise (ARC)
- Fonds National de la Recherche Scientifique (FNRS), Belgium
- European Union (project NAMIT)
- European Union (project BetaBat, in the Framework Programme 7 of the European Community)
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Components of the unfolded protein response (UPR) modulate beta cell inflammation and death in early type 1 diabetes (T1D). The UPR is a mechanism by which cells react to the accumulation of misfolded proteins in the endoplasmic reticulum (ER). It aims to restore cellular homeostasis, but in case of chronic or overwhelming ER stress the persistent activation of the UPR triggers apoptosis, contributing to the loss of beta cells in both T1D and type 2 diabetes. It remains to be determined how and why the transition from 'physiological' to 'pathological' UPR takes place. A key component of the UPR is the ER transmembrane protein IRE1 alpha (inositol-requiring enzyme 1 alpha). IRE1 alpha activity is modulated by both intra-ER signals and by the formation of protein complexes at its cytosolic domain. The amplitude and duration of IRE1 alpha signaling is critical for the transition between the adaptive and cell death programs, with particular relevance for the activation of the pro-apoptotic c-Jun N-terminal kinase (JNK) in beta cells. In the present review we discuss the available information on IRE1 alpha-regulating proteins in beta cells and their downstream targets, and the important differences observed between cytokine-induced UPR in human and rodent beta cells.
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