Objective: Transport and Golgi Organization protein 1 (TANGO1) is a protein that regulates the export of procollagen from the endoplasmic reticulum and has a role in the organization of exit sites for general protein export. What regulates the expression of TANGO1 and the role of TANGO1 in fibrosis is poorly understood and has never been studied in the setting of systemic sclerosis (SSc). We undertook this study to determine the role of TANGO1 in SSc fibrosis.
Methods: SSc (n = 15) and healthy (n = 12) primary fibroblast lung cell lines were investigated for the expression of TANGO1. Histologic analyses for TANGO1 were performed on lung biopsy samples (n = 12 SSc patient samples and n = 8 healthy control samples).
Results: SSc fibroblasts showed increased expression of TANGO1 protein in cultured fibroblasts. TANGO1 colocalizes with α-smooth muscle actin (α-SMA)-positive cells in SSc lung tissue and is highly up-regulated in the neointima of SSc vessels. TANGO1 expression was dependent on the inflammasome activation of caspase 1. It was also dependent on signaling from the interleukin-1 (IL-1) and transforming growth factor β (TGFβ) receptors. The decrease in TANGO1 down-regulated export of larger cargos including collagen and laminin. Reduced TANGO1 protein had no effect on smaller molecular weight cargoes; however, the secretion of elastin was significantly reduced.
Conclusion: TANGO1 is markedly increased in SSc fibroblasts and was found to be elevated in lung tissue in association with α-SMA-positive cells. TANGO1 expression is driven by inflammasome-dependent caspase 1 activation and is mediated by IL-1 and TGFβ downstream signaling. These observations suggest that during fibrosis, caspase 1 promotes the up-regulation of TANGO1 and the organization of endoplasmic reticulum exits sites, ultimately contributing to procollagen export and fibrosis.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543382 | PMC |
| http://dx.doi.org/10.1002/art.42535 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Dextromethorphan inhibits collagen and collagen-like cargo secretion to ameliorate lung fibrosis.
Sci Transl Med
December 2024
Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
Excessive deposition of fibrillar collagen in the interstitial extracellular matrix (ECM) of human lung tissue causes fibrosis, which can ultimately lead to organ failure. Despite our understanding of the molecular mechanisms underlying the disease, no cure for pulmonary fibrosis has yet been found. We screened a drug library and found that dextromethorphan (DXM), a cough expectorant, reduced the amount of excess fibrillar collagen deposited in the ECM in cultured primary human lung fibroblasts, a bleomycin mouse model, and a cultured human precision-cut lung slice model of lung fibrosis.
View Article and Find Full Text PDFVisualization of ER-to-Golgi trafficking of procollagen X.
Cell Struct Funct
October 2024
Laboratory of Molecular and Cellular Biology, Institute for Life and Medical Sciences, Kyoto University.
Collagen is the most abundant protein in the extracellular matrix of animals, and 28 types of collagen have been reported in humans. We previously analyzed the endoplasmic reticulum (ER)-to-Golgi transport of fibril-forming type III collagen (Hirata et al., 2022) and network-forming type IV collagen (Matsui et al.
View Article and Find Full Text PDFeffector EgeA facilitates infection by hijacking TANGO1 and SCFD1 from ER-Golgi exit sites to pathogen-occupied inclusions.
Proc Natl Acad Sci U S A
August 2024
Department of Veterinary Biosciences, College of Veterinary Medicine, Infectious Diseases Institute, The Ohio State University, Columbus, OH 43210.
The obligatory intracellular bacterium causes human granulocytic anaplasmosis, an emerging zoonosis. has limited biosynthetic and metabolic capacities, yet it effectively replicates inside of inclusions/vacuoles of eukaryotic host cells. Here, we describe a unique Type IV secretion system (T4SS) effector, R-olgi xit site protein of (EgeA).
View Article and Find Full Text PDFEndoplasmic reticulum exit sites are segregated for secretion based on cargo size.
Dev Cell
October 2024
Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; ICREA, Pg. Lluis Companys 23, Barcelona 08010, Spain. Electronic address:
Article Synopsis
- TANGO1, TANGO1-Short, and cTAGE5 work together in a place inside cells called the endoplasmic reticulum exit sites (ERES) to help move large materials out of the cell.
- TANGO1-Short has a special part that can be changed to respond to light, making it easier to control how it connects to another helper protein called Sec23A.
- The study found that when the TANGO1-Short connects to Sec23A after the light is turned on, it organizes the cargo in a way that helps sort larger materials differently from smaller ones, making it easier for the cell to release them efficiently.
TANGO1 inhibitors reduce collagen secretion and limit tissue scarring.
Nat Commun
April 2024
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, Barcelona, Spain.
Uncontrolled secretion of ECM proteins, such as collagen, can lead to excessive scarring and fibrosis and compromise tissue function. Despite the widespread occurrence of fibrotic diseases and scarring, effective therapies are lacking. A promising approach would be to limit the amount of collagen released from hyperactive fibroblasts.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!