title: IHG-1 must be localised to mitochondria to decrease Smad7 expression and amplify TGF-β1-induced fibrotic responses.
abstract: TGF-β1 is a prototypic profibrotic cytokine and major driver of fibrosis in the kidney and other organs. Induced in high glucose-1 (IHG-1) is a mitochondrial protein which we have recently reported to be associated with renal disease. IHG-1 amplifies responses to TGF-β1 and regulates mitochondrial biogenesis by stabilising the transcriptional co-activator peroxisome proliferator-activated receptor gamma coactivator-1-alpha. Here we report that the mitochondrial localisation of IHG-1 is pivotal in the amplification of TGF-β1 signalling. We demonstrate that IHG-1 expression is associated with repression of the endogenous TGF-β1 inhibitor Smad7. Intriguingly, expression of a non-mitochondrial deletion mutant of IHG-1 (Δmts-IHG-1) repressed TGF-β1 fibrotic signalling in renal epithelial cells. In cells expressing Δmts-IHG-1 fibrotic responses including CCN2/connective tissue growth factor, fibronectin and jagged-1 expression were reduced following stimulation with TGF-β1. Δmts-IHG-1 modulation of TGF-β1 signalling was associated with increased Smad7 protein expression. Δmts-IHG-1 modulated TGF-β1 activity by increasing Smad7 protein expression as it failed to inhibit TGF-β1 transcriptional responses when endogenous Smad7 expression was knocked down. These data indicate that mitochondria modulate TGF-β1 signal transduction and that IHG-1 is a key player in this modulation.
authors.affiliation: School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: James B
authors.initials: JB
authors.lastname: Corcoran
authors.forename: Sarah
authors.initials: S
authors.lastname: McCarthy
authors.forename: Brenda
authors.initials: B
authors.lastname: Griffin
authors.forename: Andrew
authors.initials: A
authors.lastname: Gaffney
authors.forename: Una
authors.initials: U
authors.lastname: Bhreathnach
authors.forename: Emma
authors.initials: E
authors.lastname: Börgeson
authors.forename: Fionnuala B
authors.initials: FB
authors.lastname: Hickey
authors.forename: Neil G
authors.initials: NG
authors.lastname: Docherty
authors.forename: Debra F
authors.initials: DF
authors.lastname: Higgins
authors.forename: Fiona
authors.initials: F
authors.lastname: Furlong
authors.forename: Finian
authors.initials: F
authors.lastname: Martin
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
authors.forename: Madeline
authors.initials: M
authors.lastname: Murphy
mesh_terms: D000595:Amino Acid Sequence; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D007668:Kidney / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D051906:Smad7 Protein / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C526317:CCN2 protein, human; D002135:Calcium-Binding Proteins; D005353:Fibronectins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D011506:Proteins; C497806:SMAD7 protein, human; D000072099:Serrate-Jagged Proteins; D051906:Smad7 Protein; C532028:THG1L protein, human; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor