title: The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice.
abstract: Fibrogenesis encompasses the deposition of matrix proteins, such as collagen I, by hepatic stellate cells (HSCs) that culminates in cirrhosis. Fibrogenic signals drive transcription of procollagen I, which enters the endoplasmic reticulum (ER), is trafficked through the secretory pathway, and released to generate extracellular matrix. Alternatively, disruption of procollagen I ER export could activate the unfolded protein response (UPR) and drive HSC apoptosis. Using a small interfering RNA screen, we identified Transport and Golgi organization 1 (TANGO1) as a potential participant in collagen I secretion. We investigated the role of TANGO1 in procollagen I secretion in HSCs and liver fibrogenesis. Depletion of TANGO1 in HSCs blocked collagen I secretion without affecting other matrix proteins. Disruption of secretion led to procollagen I retention within the ER, induction of the UPR, and HSC apoptosis. In wild-type (WT) HSCs, both TANGO1 and the UPR were induced by transforming growth factor β (TGFβ). As the UPR up-regulates proteins involved in secretion, we studied whether TANGO1 was a target of the UPR. We found that UPR signaling is responsible for up-regulating TANGO1 in response to TGFβ, and this mechanism is mediated by the transcription factor X-box binding protein 1 (XBP1). In vivo, murine and human cirrhotic tissue displayed increased TANGO1 messenger RNA levels. Finally, TANGO1+/-mice displayed less hepatic fibrosis compared to WT mice in two separate murine models: CCl4and bile duct ligation.
  
  
  
  Loss of TANGO1 leads to procollagen I retention in the ER, which promotes UPR-mediated HSC apoptosis. TANGO1 regulation during HSC activation occurs through a UPR-dependent mechanism that requires the transcription factor, XBP1. Finally, TANGO1 is critical for fibrogenesis through mediating HSC homeostasis. The work reveals a unique role for TANGO1 and the UPR in facilitating collagen I secretion and fibrogenesis. (Hepatology 2017;65:983-998).
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Maiers
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Enis
authors.initials: E
authors.lastname: Kostallari
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Malek
authors.initials: M
authors.lastname: Mushref
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: deAssuncao
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Jalan-Sakrikar
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Huebert
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Sheng
authors.initials: S
authors.lastname: Cao
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Harmeet
authors.initials: H
authors.lastname: Malhi
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Vijay H
authors.initials: VH
authors.lastname: Shah
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism*; D001597:Benzylidene Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology; D015151:Immunoblotting; D008103:Liver Cirrhosis / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction / Q000379:methods; D011897:Random Allocation; D012680:Sensitivity and Specificity; D056811:Unfolded Protein Response / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D001597:Benzylidene Compounds; D024042:Collagen Type I; D006827:Hydantoins; C495722:TANGO protein, mouse; C528478:UPR1024; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator