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Title: Ubiquitin D Regulates IRE1 alpha/c-Jun N-terminal Kinase (JNK) Protein-dependent Apoptosis in Pancreatic Beta Cells
Authors: Brozzi, Flora ×
Gerlo, Sarah
Grieco, Fabio Arturo
Juusola, Matilda
Balhuizen, Alexander
Lievens, Sam
Gysemans, Conny
Bugliani, Marco
Mathieu, Chantal
Marchetti, Piero
Tavernier, Jan
Eizirik, Decio L #
Issue Date: Jun-2016
Publisher: American Society for Biochemistry and Molecular Biology
Series Title: Journal of Biological Chemistry vol:291 issue:23 pages:12040-12056
Article number: jbc.M115.704619
Abstract: Pro-inflammatory cytokines contribute to pancreatic beta cell apoptosis in type 1 diabetes (T1D) at least in part by inducing endoplasmic reticulum (ER) stress and the consequent unfolded protein response (UPR). It remains to be determined what causes the transition from ″physiological″ to ″apoptotic″ UPR, but accumulating evidence indicates that signaling by the ER transmembrane protein IRE1α is critical for this transition. IRE1α activation is regulated by both intra ER and cytosolic cues. We evaluated the role for the presently discovered cytokine-induced and IRE1α-interacting protein, Ubiquitin D (UBD) on the regulation of IRE1α and its dowstream targets. UBD was identified by use of a MAPPIT (MAmmalian Protein-Protein Interaction Trap)-based IRE1α interactome screen followed by comparison against functional genomic analysis of human and rodent beta cells exposed to pro-inflammatory cytokines. Knock down (KD) of UBD in human and rodent beta cells and detailed signal transduction studies indicated that UBD modulates cytokine-induced UPR/ IRE1α activation and apoptosis. UBD expression is induced by the pro-inflammatory cytokines interleukin (IL)-1β and interferon (IFN)-γ in rat and human pancreatic beta cells and it is also up-regulated in beta cells of inflamed islets from NOD mice. UBD interacts with IRE1α in human and rodent beta cells, modulating IRE1α-dependent activation of JNK and cytokine-induced apoptosis. Our data suggest that UBD provides a negative feedback on cytokine-induced activation of the IRE1α/JNK pro-apoptotic pathway in cytokine-exposed beta cells.
URI: 
ISSN: 0021-9258
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Near Eastern Studies, Leuven
Clinical and Experimental Endocrinology
× corresponding author
# (joint) last author

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