title: Autophagy promotes intracellular degradation of type I collagen induced by transforming growth factor (TGF)-β1.
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.
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Sung Il
authors.initials: SI
authors.lastname: Kim
authors.forename: Hee-Jun
authors.initials: HJ
authors.lastname: Na
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Wang
authors.forename: Seon Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Mary E
authors.initials: ME
authors.lastname: Choi
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics; D001343:Autophagy; D000071186:Beclin-1; D002248:Carbon Monoxide / Q000494:pharmacology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D059748:Proteolysis; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D002248:Carbon Monoxide; D024042:Collagen Type I; D020930:MAP Kinase Kinase Kinases; D008869:Microtubule-Associated Proteins; D053773:Transforming Growth Factor beta1; D000099151:MAP Kinase Kinase Kinase 7; C115010:Becn1 protein, mouse; C480860:Map1lc3b protein, mouse