Tango1 assembles a machine for collagen folding and export

• Autores: Anupama Ashok
• Directores de la Tesis: Vivek Malhotra (dir. tes.)
• Lectura: En la Universitat Pompeu Fabra ( España ) en 2019
• Idioma: español
• Tribunal Calificador de la Tesis: Carles Enrich Bastús (presid.), Miguel Ángel Valverde De Castro (secret.), Juan Valcárcel Juárez (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad Pompeu Fabra
• Materias:
  • Ciencias de la vida
    • Biología celular
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • COPII vesicles of 60-90nm diameter are known to export secretory cargoes from endoplasmic reticulum (ER). However, they cannot be employed to export bulky cargoes like the collagens that can reach up to 400 nm in length. Collagens, the most abundant secretory proteins, make up 25% of our dry body weight and required for building extracellular matrix, and to produce mineralized bones. The discovery TANGO1 has made the process of collagen export at the ER amenable to molecular analysis. I set out to identify its interactors through a proximity biotinylation coupled with mass spectrometry approach. My results show that TANGO1 bridges the cytoplasmic export machinery with ER luminal folding machinery. It is noteworthy that several of the luminal interactors identified are exclusively dedicated to collagen folding and modification. This search also revealed the identity of protein called Torsin-1A, and my data show that it potentially functions in degrading unfolded collagens. I also asked whether TANGO1 is required to export transmembrane collagens. Transmembrane collagens are unique as they have a cytoplasmic domain that can in theory recruit COPII proteins to facilitate their export. I observed minimal dependency on TANGO1 for transmembrane collagen XVII export. Interestingly, TANGO1 binds both folded and misfolded Collagen XVII.

    Altogether, my data suggest that TANGO1 functions predominantly to export soluble collagens its ability to bind both folded and unfolded collagens is used by the cells to eliminate unfolded collagens and to ensure only the full assembled and functional collagen are secreted.