title: Deficiency of the BiP cochaperone ERdj4 causes constitutive endoplasmic reticulum stress and metabolic defects.
abstract: Endoplasmic reticulum-localized DnaJ 4 (ERdj4) is an immunoglobulin-binding protein (BiP) cochaperone and component of the endoplasmic reticulum-associated degradation (ERAD) pathway that functions to remove unfolded/misfolded substrates from the ER lumen under conditions of ER stress. To elucidate the function of ERdj4 in vivo, we disrupted the ERdj4 locus using gene trap (GT) mutagenesis, leading to hypomorphic expression of ERdj4 in mice homozygous for the trapped allele (ERdj4(GT/GT)). Approximately half of ERdj4(GT/GT) mice died perinatally associated with fetal growth restriction, reduced hepatic glycogen stores, and hypoglycemia. Surviving adult mice exhibited evidence of constitutive ER stress in multiple cells/tissues, including fibroblasts, lung, kidney, salivary gland, and pancreas. Elevated ER stress in pancreatic β cells of ERdj4(GT/GT) mice was associated with β cell loss, hypoinsulinemia, and glucose intolerance. Collectively these results suggest an important role for ERdj4 in maintaining ER homeostasis during normal fetal growth and postnatal adaptation to metabolic stress.
authors: Perinatal Institute, Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, and University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors: Jill M
authors: JM
authors: Fritz
authors: Mei
authors: M
authors: Dong
authors: Karen S
authors: KS
authors: Apsley
authors: Emily P
authors: EP
authors: Martin
authors: Cheng-Lun
authors: CL
authors: Na
authors: Sneha
authors: S
authors: Sitaraman
authors: Timothy E
authors: TE
authors: Weaver
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003433:Crosses, Genetic; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005260:Female; D005313:Fetal Death; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D020043:Genes, Essential; D056426:Genetic Loci; D018149:Glucose Intolerance; D006003:Glycogen / Q000172:deficiency; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D007003:Hypoglycemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000172:deficiency; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016296:Mutagenesis; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; C458526:ERdj4 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007328:Insulin; D008562:Membrane Glycoproteins; D006003:Glycogen