Ubiquitin D regulates IRE1 α/c-Jun N-terminal kinase (JNK) protein-dependent apoptosis in pancreatic beta cells
| Autor: | Conny C Gysemans, Piero Marchetti, Alexander Balhuizen, Decio L. Eizirik, Sam Lievens, Matilda M Juusola, Fabio Arturo Grieco, Jan Tavernier, Sarah Gerlo, Marco Bugliani, Chantal Mathieu, Flora Brozzi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male type 1 diabetes Gene Expression Apoptosis Cytokines -- pharmacology Biochemistry Gene Expression -- drug effects ENDOPLASMIC-RETICULUM STRESS Interferon Insulin-Secreting Cells IRE1α apoptosis c-Jun N-terminal kinase (JNK) cytokinesis endoplasmic reticulum stress (ER stress) ubiquitin D Aged Aged 80 and over Animals Blotting Western Cell Line Cell Line Tumor Cells Cultured Cytokines Endoribonucleases Female HEK293 Cells Humans JNK Mitogen-Activated Protein Kinases Middle Aged Protein Binding Protein-Serine-Threonine Kinases RNA Interference Rats Reverse Transcriptase Polymerase Chain Reaction Ubiquitins Young Adult Molecular Biology Cell Biology 80 and over Ubiquitin D GENE-EXPRESSION Tumor Cultured Blotting Kinase c-jun JNK Mitogen-Activated Protein Kinases -- metabolism Molecular Bases of Disease Protein-Serine-Threonine Kinases -- genetics -- metabolism Sciences bio-médicales et agricoles Cell biology FACTOR-KAPPA-B Ubiquitins -- genetics -- metabolism Signal transduction Western medicine.drug CANDIDATE GENE Endoribonucleases -- genetics -- metabolism Cells SIGNAL-TRANSDUCTION Protein Serine-Threonine Kinases Biology 03 medical and health sciences medicine Insulin-Secreting Cells -- drug effects -- metabolism INTERFERON-GAMMA Endoplasmic reticulum HEK 293 cells CYTOKINES Biology and Life Sciences NECROSIS-FACTOR-ALPHA DIABETES-MELLITUS Molecular biology MAJOR HISTOCOMPATIBILITY COMPLEX 030104 developmental biology Unfolded protein response |
| Zdroj: | JOURNAL OF BIOLOGICAL CHEMISTRY The Journal of biological chemistry, 291 (23 |
| ISSN: | 0021-9258 |
| Popis: | Pro-inflammatory cytokines contribute to pancreatic beta cell apoptosis in type 1 diabetes 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 downstream 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. Knockdown 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 non-obese diabetic 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. info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|