IHG-1 must be localised to mitochondria to decrease Smad7 expression and amplify TGF-β1-induced fibrotic responses

被引：23

作者：

Corcoran, James B. ^{[1
]}

McCarthy, Sarah ^{[1
]}

Griffin, Brenda ^{[1
]}

Gaffney, Andrew ^{[1
]}

Bhreathnach, Una ^{[1
]}

Boergeson, Emma ^{[1
]}

Hickey, Fionnuala B. ^{[1
]}

Docherty, Neil G. ^{[2
]}

Higgins, Debra F. ^{[1
]}

Furlong, Fiona ^{[1
,3
]}

Martin, Finian ^{[1
]}

Godson, Catherine ^{[1
]}

Murphy, Madeline ^{[1
]}

机构：

[1] Natl Univ Ireland Univ Coll Dublin, Sch Med & Med Sci, UCD Conway Inst, UCD Diabet Complicat Res Ctr, Dublin 4, Ireland

[2] Trinity Coll Dublin, Trinity Biomed Sci Inst, Sch Med, Dept Physiol, Dublin, Ireland

[3] Queens Univ Belfast, Sch Pharm, Belfast BT9 7BL, Antrim, North Ireland

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH | 2013年 / 1833卷 / 08期

基金：

爱尔兰科学基金会; 英国惠康基金;

关键词：

IHG-1; TGF-beta; 1; Mitochondria; Smad7; GROWTH-FACTOR-BETA; OXIDATIVE STRESS; MESANGIAL CELLS; RENAL FIBROSIS; NUCLEAR EXPORT; RECEPTOR; DISEASE; SMURF1; INFLAMMATION; ACETYLATION;

D O I：

10.1016/j.bbamcr.2013.03.027

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

TGF-beta 1 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-beta 1 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-beta 1 signalling. We demonstrate that IHG-1 expression is associated with repression of the endogenous TGF-beta 1 inhibitor Smad7. Intriguingly, expression of a non-mitochondrial deletion mutant of IHG-1 (Delta mts-IHG-1) repressed TGF-beta 1 fibrotic signalling in renal epithelial cells. In cells expressing Delta mts-IHG-1 fibrotic responses including CCN2/connective tissue growth factor, fibronectin and jagged-1 expression were reduced following stimulation with TGF-beta 1. Delta mts-IHG-1 modulation of TGF-beta 1 signalling was associated with increased Smad7 protein expression. Delta mts-IHG-1 modulated TGF-beta 1 activity by increasing Smad7 protein expression as it failed to inhibit TGF-beta 1 transcriptional responses when endogenous Smad7 expression was knocked down. These data indicate that mitochondria modulate TGF-beta 1 signal transduction and that IHG-1 is a key player in this modulation. (C) 2013 Elsevier B.V. All rights reserved.

引用

页码：1969 / 1978

页数：10

共 51 条

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