| First Author | Kim SI | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 15 | Pages | 11677-88 |
| PubMed ID | 22351764 | Mgi Jnum | J:184288 |
| Mgi Id | MGI:5320684 | Doi | 10.1074/jbc.M111.308460 |
| Citation | Kim SI, et al. (2012) Autophagy promotes intracellular degradation of type I collagen induced by transforming growth factor (TGF)-beta1. J Biol Chem 287(15):11677-88 |
| abstractText | 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-beta1, without alterations in Col-I alpha1 mRNA. Heterozygous deletion of beclin 1 increased accumulation of aggregated Col-I under nonstimulated conditions, and stimulation with TGF-beta1 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-beta1. We also show that TGF-beta1 induces autophagy in MMC via TAK1-MKK3-p38 signaling pathway. The dual functions of TGF-beta1, as both an inducer of Col-I synthesis and an inducer of autophagy and Col-I degradation, underscore the multifunctional nature of TGF-beta1. Our findings suggest a novel role of autophagy as a cytoprotective mechanism to negatively regulate and prevent excess collagen accumulation in the kidney. |
