Caspase 1 Enhances Transport and Golgi Organization Protein 1 Expression to Promote Procollagen Export From the Endoplasmic Reticulum in Systemic Sclerosis Contributing to Fibrosis

Abstract

ObjectiveTANGO1 (Transport ANd Golgi Organization protein 1) 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 its role in fibrosis, is poorly understood, and has never been studied in systemic sclerosis (SSc). We undertook these studies to determine the role for TANGO1 in SSc fibrosis.MethodsSSc (n=15) and healthy (n=12) primary fibroblast lung cell lines were investigated for the expression of TANGO1. Histological analyses for TANGO1 were performed on lung biopsies (n=12 SSc and n=8 healthy).ResultsSSc fibroblasts show increased TANGO1 protein in cultured fibroblasts. TANGO1 colocalizes with α‐SMA positive cells in SSc lung tissue and is highly upregulated 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 IL‐1 and TGF‐β receptors. The decrease in TANGO1 downregulated 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.ConclusionTANGO1 is markedly increased in SSc fibroblasts and found 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 TGF‐β downstream signaling. These observations suggest that during fibrosis, caspase‐1 promotes the upregulation of TANGO1, and the organization of ER exits sites, ultimately contributing to procollagen export and fibrosis.This article is protected by copyright. All rights reserved.image

Fundamental transport mechanism of mucin-2 ER-to-Golgi trafficking identifies source of ER stress in inflammatory bowel disease

“…TGF-β has been implicated in IBD as lower active levels are observed (76), due to increased expression of TGF-β inhibitor Smad7 in the intestinal mucosa (77, 78), prompting us to investigate the effect of TGF-β on mucin-2 trafficking. Consistent with previous research (36, 79), TGF-β induced expression of TANGO1. The effect of inhibiting TGF-β on TANGO1 has not been reported previously, however, the decreased expression is in line as an antagonistic response to TGF-β stimulation.…”

“…Generally, post-transcriptional and post-translational modifications play an important role in the formation of large COPII vesicles (92). Recently, it was shown that TANGO1 expression was dependent on inflammasome activation of caspase-1, as well as signaling from IL-1 and TGF-β (79). Elucidating the post-transcriptional mechanism of TANGO1, possibly mediated by TGF-β, could identify therapeutic targets for IBD and fibrosis.…”