Lysosomal trafficking of TGFBIp via caveolae-mediated endocytosis

• Published in: PloS one Vol. 10; no. 4; p. e0119561
• Main Authors: Choi, Seung-Il, Maeng, Yong-Sun, Kim, Tae-Im, Lee, Yangsin, Kim, Yong-Sun, Kim, Eung Kweon
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.04.2015; Public Library of Science (PLoS)
• Subjects: Adolescent; Adult; Aging; Amino Acid Motifs; Arginine; Aspartic acid; Autophagy; Caveolae; Caveolae - metabolism; Cell adhesion & migration; Cell lines; Child; Cornea; Corneal Diseases - pathology; Corneal dystrophy; Dystrophy; Endocytosis; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Extracellular matrix; Extracellular Matrix Proteins - chemistry; Extracellular Matrix Proteins - metabolism; Female; Fibroblasts; Fibroblasts - cytology; Fibroblasts - pathology; Gene mutation; Genetic aspects; Glycine; Golgi apparatus; Golgi Apparatus - metabolism; Growth factors; Humans; Immunoprecipitation; Inhibitors; Integrin alphaVbeta3 - metabolism; Internalization; Lysosomes; Lysosomes - metabolism; Male; Medicine; Mutation; Pathogenesis; Physiological aspects; Plasma; Proteasome Endopeptidase Complex - metabolism; Proteasome inhibitors; Proteins; Proteolysis; Route selection; Science; Target recognition; Transforming Growth Factor beta - chemistry; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Transforming growth factors; Ubiquitin - metabolism; Young Adult; South Korea; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0119561

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.