Inhibition of deoxyhypusine synthase enhances islet {beta} cell function and survival in the setting of endoplasmic reticulum stress and type 2 diabetes.
Islet β cell dysfunction resulting from inflammation, ER stress, and oxidative stress is a key determinant in the progression from insulin resistance to type 2 diabetes mellitus. It was recently shown that the enzyme deoxyhypusine synthase (DHS) promotes early cytokine-induced inflammation in the β cell. DHS catalyzes the conversion of lysine to hypusine, an amino acid that is unique to the translational elongation factor eIF5A. Here, we sought to determine whether DHS activity contributes to β cell dysfunction in models of type 2 diabetes in mice and β cell lines. A 2-week treatment of obese diabetic C57BLKS/J-db/db mice with the DHS inhibitor GC7 resulted in improved glucose tolerance, increased insulin release, and enhanced β cell mass. Thapsigargin treatment of β cells in vitro induces a picture of ER stress and apoptosis similar to that seen in db/db mice; in this setting, DHS inhibition led to a block in CHOP (CAAT/enhancer binding protein homologous protein) production despite >30-fold activation of Chop gene transcription. Blockage of CHOP translation resulted in reduction of downstream caspase-3 cleavage and near-complete protection of cells from apoptotic death. DHS inhibition appeared to prevent the cytoplasmic co-localization of eIF5A with the ER, possibly precluding the participation of eIF5A in translational elongation at ER-based ribosomes. We conclude that hypusination by DHS is required for the ongoing production of proteins, particularly CHOP, in response to ER stress in the β cell.
Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22904, USA.
Reiesha D
RD
Robbins
Sarah A
SA
Tersey
Takeshi
T
Ogihara
Dhananjay
D
Gupta
Thomas B
TB
Farb
James
J
Ficorilli
Krister
K
Bokvist
Bernhard
B
Maier
Raghavendra G
RG
Mirmira
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics / Q000378:metabolism*; D010441:Peptide Chain Elongation, Translational / Q000187:drug effects / Q000235:genetics; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics; D056811:Unfolded Protein Response; D000097574:Eukaryotic Translation Initiation Factor 5A
D053148:Caspase 3; D004791:Enzyme Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors; D010448:Peptide Initiation Factors; D016601:RNA-Binding Proteins; D019284:Thapsigargin; D051742:Transcription Factor CHOP; D000097574:Eukaryotic Translation Initiation Factor 5A; C497250:Ddit3 protein, mouse; C063507:deoxyhypusine synthase; C505409:Casp3 protein, mouse