ER-associated degradation is required for the maintenance of β cell identity via TGFβ signaling

  • Neha Shrestha (Creator)
  • T. Liu (Creator)
  • Yewei Ji (Creator)
  • Rachel B. Reinert (Creator)
  • Mauricio Torres (Creator)
  • M. Zhang (Creator)
  • C.A. Tang (Creator)
  • C.A. Hu (Creator)
  • Chengyang Liu (Creator)
  • Ali Naji (Creator)
  • Jiandie D. Lin (Creator)
  • Sander Kersten (Creator)
  • Peter Arvan (Creator)
  • Ling Qi (Creator)
  • Guido Hooiveld (Contributor)

Dataset

Description

β cell apoptosis and dedifferentiation are two hotly-debated mechanisms underlying β cell loss in type 2 diabetes (T2D); however, the molecular drivers underlying such events remain largely unclear. Here, by performing a side-by-side comparison of mice carrying β cell-specific deletion of endoplasmic reticulum (ER)-associated degradation (ERAD) and autophagy, we report that while autophagy appears necessary for β cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex is required for the maintenance of β cell maturation and identity. Notably, SEL1L expression is significantly reduced in human T2D islets compared to healthy human islets. At the single cell level, we demonstrate that Sel1L deficiency is not associated with β cell loss, but rather loss of β cell identity. Mechanistically, we find that Sel1L-Hrd1 ERAD controls β cell identity via TGFβ signaling, in part by mediating the degradation of TGF-β receptor 1 (TGFβRI). Inhibition of TGFβ signaling in Sel1L-deficient β cells augments the expression of β cell maturation markers and increases the total insulin content. Our data reveal profound but distinct pathogenic effects of two major proteolytic pathways in β cells, providing a new framework for therapies targeting distinct mechanisms of protein quality control
Date made available29 Jun 2020
PublisherWageningen University & Research

Research Output

Sel1L-Hrd1 ER-associated degradation maintains β cell identity via TGF-β signaling

Shrestha, N., Liu, T., Ji, Y., Reinert, R. B., Torres, M., Li, X., Zhang, M., Tang, C-H. A., Hu, C-C. A., Liu, C., Naji, A., Liu, M., Lin, J. D., Kersten, S., Arvan, P. & Qi, L., 1 Jul 2020, In : The Journal of Clinical Investigation. 130, 7, p. 3499-3510

Research output: Contribution to journalArticleAcademicpeer-review

  • 1 Citation (Scopus)

    Cite this

    Shrestha, N. (Creator), Liu, T. (Creator), Ji, Y. (Creator), Reinert, R. B. (Creator), Torres, M. (Creator), Zhang, M. (Creator), Tang, C. A. (Creator), Hu, C. A. (Creator), Liu, C. (Creator), Naji, A. (Creator), Lin, J. D. (Creator), Kersten, S. (Creator), Arvan, P. (Creator), Qi, L. (Creator), Hooiveld, G. (Contributor) (29 Jun 2020). ER-associated degradation is required for the maintenance of β cell identity via TGFβ signaling. Wageningen University & Research.