title: Nedd4 family interacting protein 1 (Ndfip1) promotes death of pancreatic beta cells.
abstract: High-throughput siRNA screening was employed to identify novel genes that regulate cytokine-induced death of pancreatic β-cells. One of the 'hits' was Nedd4 family interacting protein 1 (Ndfip1), an adaptor and activator of Nedd4-family ubiquitin ligases. Silencing of Ndfip1 inhibited cytokine-induced apoptosis of mouse and human pancreatic islets and promoted glucose-stimulated insulin secretion. These effects were associated with an increase in the cellular content of JunB, a potent inhibitor of ER stress and apoptosis. Silencing of Ndfip1 also increased the expression of ATF4, IRE-1α, and the spliced form of XBP that govern the unfolded protein response (UPR) and relieve cytokine-induced ER stress, while overexpression of Ndfip1 exerted opposite effects. These findings implicate Ndfip1 in the degradation of JunB; inhibition of the UPR and insulin secretion; and promotion of cytokine-induced death of pancreatic β-cells.
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Avital
authors: A
authors: Beck
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Hadas
authors: H
authors: Shatz-Azoulay
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Yaron
authors: Y
authors: Vinik
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Roi
authors: R
authors: Isaac
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Sigalit
authors: S
authors: Boura-Halfon
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: Yehiel.Zick@weizmann.ac.il.
authors: Yehiel
authors: Y
authors: Zick
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D057166:High-Throughput Screening Assays; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; C581727:JunB protein, human; C584097:JunB protein, mouse; D008565:Membrane Proteins; C451223:NDFIP1 protein, human; C499188:Ndfip1 protein, mouse; D034741:RNA, Small Interfering; D014157:Transcription Factors
keywords: Cytokines; JunB; Ndfip1; Pancreatic beta cells; Unfolded protein response