RRC ID 27897
Author Kim SI, Na HJ, Ding Y, Wang Z, Lee SJ, Choi ME.
Title Autophagy promotes intracellular degradation of type I collagen induced by transforming growth factor (TGF)-β1.
Journal J Biol Chem
Abstract Autophagy is a highly conserved cellular process regulating turnover of cytoplasmic proteins via a lysosome-dependent pathway. Here we show that kidneys from mice deficient in autophagic protein Beclin 1 exhibited profibrotic phenotype, with increased collagen deposition. Reduced Beclin 1 expression, through genetic disruption of beclin 1 or knockdown by specific siRNA in primary mouse mesangial cells (MMC), resulted in increased protein levels of type I collagen (Col-I). Inhibition of autolysosomal protein degradation by bafilomycin A(1) also increased Col-I protein levels and colocalization of Col-I with LC3, an autophagy marker, or LAMP-1, a lysosome marker, whereas treatment with TFP, an inducer of autophagy, resulted in decreased Col-I protein levels induced by TGF-β1, without alterations in Col-I α1 mRNA. Heterozygous deletion of beclin 1 increased accumulation of aggregated Col-I under nonstimulated conditions, and stimulation with TGF-β1 further increased aggregated Col-I. These data indicate that Col-I and aggregated, insoluble procollagen I undergo intracellular degradation via autophagy. A cytoprotective role of autophagy is implicated in kidney injury, and we demonstrate that low-dose carbon monoxide, shown to exert cytoprotection against renal fibrosis, induces autophagy to suppress accumulation of Col-I induced by TGF-β1. We also show that TGF-β1 induces autophagy in MMC via TAK1-MKK3-p38 signaling pathway. The dual functions of TGF-β1, as both an inducer of Col-I synthesis and an inducer of autophagy and Col-I degradation, underscore the multifunctional nature of TGF-β1. Our findings suggest a novel role of autophagy as a cytoprotective mechanism to negatively regulate and prevent excess collagen accumulation in the kidney.
Volume 287(15)
Pages 11677-88
Published 2012-4-6
DOI 10.1074/jbc.M111.308460
PII M111.308460
PMID 22351764
PMC PMC3320917
MeSH Animals Apoptosis Regulatory Proteins / deficiency Apoptosis Regulatory Proteins / genetics Autophagy* Beclin-1 Carbon Monoxide / pharmacology Cells, Cultured Collagen Type I / genetics Collagen Type I / metabolism* Kidney / cytology Kidney / metabolism MAP Kinase Kinase Kinases / metabolism MAP Kinase Signaling System Male Mesangial Cells / metabolism Mesangial Cells / physiology Mice Mice, Inbred C57BL Mice, Transgenic Microtubule-Associated Proteins / metabolism Proteolysis* Transforming Growth Factor beta1 / metabolism Transforming Growth Factor beta1 / physiology*
IF 4.106
Times Cited 133
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
Mice GFP-LC3#53(RBRC00806)