title: Lysosomal trafficking of TGFBIp via caveolae-mediated endocytosis.
abstract: Transforming growth factor-beta-induced protein (TGFBIp) is ubiquitously expressed in the extracellular matrix (ECM) of various tissues and cell lines. Progressive accumulation of mutant TGFBIp is directly involved in the pathogenesis of TGFBI-linked corneal dystrophy. Recent studies reported that mutant TGFBIp accumulates in cells; however, the trafficking of TGFBIp is poorly understood. Therefore, we investigated TGFBIp trafficking to determine the route of its internalization and secretion and to elucidate its roles in the pathogenesis of granular corneal dystrophy type 2 (GCD2). Our data indicate that newly synthesized TGFBIp was secreted via the endoplasmic reticulum/Golgi-dependent secretory pathway, and this secretion was delayed in the corneal fibroblasts of patients with GCD2. We also found that TGFBIp was internalized by caveolae-mediated endocytosis, and the internalized TGFBIp accumulated after treatment with bafilomycin A1, an inhibitor of lysosomal degradation. In addition, the proteasome inhibitor MG132 inhibits the endocytosis of TGFBIp. Co-immunoprecipitation revealed that TGFBIp interacted with integrin αVβ3. Moreover, treatment with arginine-glycine-aspartic acid (RGD) tripeptide suppressed the internalization of TGFBIp. These insights on TGFBIp trafficking could lead to the identification of novel targets and the development of new therapies for TGFBI-linked corneal dystrophy.
authors: Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
authors: Seung-Il
authors: SI
authors: Choi
authors: Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
authors: Yong-Sun
authors: YS
authors: Maeng
authors: Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, South Korea; Institute of Vision Research, Severance Biomedical Science Institute, Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
authors: Tae-Im
authors: TI
authors: Kim
authors: Department of Integrated Omics for Biomedical Science, Graduate School, Yonsei University, Seoul, South Korea.
authors: Yangsin
authors: Y
authors: Lee
authors: Ilsong Institute of Life Science, Hallym University, Anyang, South Korea; Department of Microbiology, College of Medicine, Hallym University, Chuncheon, South Korea.
authors: Yong-Sun
authors: YS
authors: Kim
authors: Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, South Korea; Institute of Vision Research, Severance Biomedical Science Institute, Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
authors: Eung Kweon
authors: EK
authors: Kim
mesh_terms: D000293:Adolescent; D000328:Adult; D020816:Amino Acid Motifs; D021941:Caveolae / Q000378:metabolism*; D002648:Child; D003316:Corneal Diseases / Q000473:pathology; D004705:Endocytosis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D055815:Young Adult; D000099222:betaIG-H3 Protein
chemical_list: D016326:Extracellular Matrix Proteins; D039302:Integrin alphaVbeta3; D046988:Proteasome Endopeptidase Complex; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; D000099222:betaIG-H3 Protein