title: Profibrotic IHG-1 complexes with renal disease associated HSPA5 and TRAP1 in mitochondria.
abstract: The highly conserved mitochondrial protein induced in high glucose-1 (IHG-1) functions to maintain mitochondrial quality and is associated with the development of fibrosis in diabetic nephropathy. Towards identifying novel approaches to treating diabetic kidney disease, IHG-1-protein-protein interactions were investigated using epitope-tagged immunoprecipitation analyses followed by mass spectrometry. Here we show that IHG-1 is solely expressed in mitochondria and localised to the inner mitochondrial membrane, the region where mitochondrial reactive oxygen species are generated. Chaperones HSPA5 and TRAP1 and cold shock protein YBX1 were identified as IHG-1 binding partners. All three proteins are important in the cellular response to oxidative stress and play important roles in mitochondrial transcription and DNA repair. Both redox imbalance and IHG-1 stimulate TGF-β signalling. IHG-1, HSPA5 and YBX1 all show increased expression in diabetic nephropathy, chronic kidney disease and in the Unilateral Ureteral Obstruction model of kidney fibrosis. Increased IHG-1 expression in UUO correlated with loss of TRAP1 expression. IHG-1 may target TRAP1 for degradation. When IHG-1 is no longer localised to mitochondria, it retains the ability to interact with the cold shock protein YBX1, facilitating anti-fibrotic actions in the nucleus. Targeting these proteins may offer alternative treatments for fibrotic kidney disease.
authors.affiliation: Conway Institute, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Una
authors.initials: U
authors.lastname: Bhreathnach
authors.affiliation: Conway Institute, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Brenda
authors.initials: B
authors.lastname: Griffin
authors.affiliation: Conway Institute, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Eoin
authors.initials: E
authors.lastname: Brennan
authors.affiliation: Conway Institute, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Leah
authors.initials: L
authors.lastname: Ewart
authors.affiliation: Conway Institute, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Debra
authors.initials: D
authors.lastname: Higgins
authors.affiliation: Conway Institute, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland. Electronic address: madeline.murphy@ucd.ie.
authors.forename: Madeline
authors.initials: M
authors.lastname: Murphy
mesh_terms: D000091342:Endoplasmic Reticulum Chaperone BiP; D005355:Fibrosis; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D051840:Y-Box-Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D018841:HSP90 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D011506:Proteins; C532028:THG1L protein, human; C092306:TRAP1 protein, human; D016212:Transforming Growth Factor beta; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human
keywords: Chronic kidney disease; Diabetic nephropathy; HSPA5; IHG-1; Mitochondria; Oxidative stress; Respiration; TRAP1; Unilateral Ureteral Obstruction