IHG-1 must be localised to mitochondria to decrease Smad7 expression and amplify TGF-β1-induced fibrotic responses
Data(s) |
2013
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Resumo |
TGF-ß1 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-ß1 and regulates mitochondrial biogenesis by stabilising the transcriptional co-activator peroxisome proliferator-activated receptor gamma coactivator-1-alpha. Here we report that the mitochondrial localization of IHG-1 is pivotal in amplification of TGF-ß1 signaling. We demonstrate that IHG-1 expression is associated with repression of the endogenous TGF-ß1 inhibitor Smad7. Intriguingly, expression of a non-mitochondrial deletion mutant of IHG-1 (?mts-IHG-1) repressed TGF-ß1 fibrotic signaling in renal epithelial cells. In cells expressing ?mts-IHG-1 fibrotic responses including CCN2/connective tissue growth factor, fibronectin and jagged-1 expression were reduced following stimulation with TGF-ß1. ?mts-IHG-1 modulation of TGF-ß1 signaling was associated with increased Smad7 protein expression. ?mts-IHG-1 modulated TGF-ß1 activity by increasing Smad7 protein expression as it failed to inhibit TGF-ß1 transcriptional responses when endogenous Smad7 expression was knocked down. These data indicate that mitochondria modulate TGF-ß1 signal transduction and that IHG-1 is a key player in this modulation. |
Identificador | |
Idioma(s) |
eng |
Direitos |
info:eu-repo/semantics/restrictedAccess |
Fonte |
Corcoran , J B , McCarthy , S , Griffin , B , Gaffney , A , Bhreathnach , U , Börgeson , E , Hickey , F B , Docherty , N G , Higgins , D F , Furlong , F , Martin , F , Godson , C & Murphy , M 2013 , ' IHG-1 must be localised to mitochondria to decrease Smad7 expression and amplify TGF-β1-induced fibrotic responses ' Biochimica et biophysica acta . DOI: 10.1016/j.bbamcr.2013.03.027 |
Tipo |
article |