Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-located pro-tein with cytoprotective effects in neurons and pancreatic b cells in vitro and in models of neurodegeneration and diabetes in vivo. However, the exact mode of MANF action has remained elusive. Here, we show that MANF directly interacts with the ER transmembrane unfolded protein response (UPR) sensor IRE1a, and we identify the binding interface between MANF and IRE1a. The expression of wild-type MANF, but not its IRE1a binding-deficient mutant, attenuates UPR signaling by decreasing IRE1a oligomerization; phosphor-ylation; splicing of Xbp1, Atf6, and Txnip levels; and protecting neurons from ER stress-induced death. MANF-IRE1a interaction and not MANF-BiP interaction is crucial for MANF pro-survival activity in neurons in vitro and is required to protect dopamine neurons in an animal model of Parkinson's disease. Our data show IRE1a as an intracellular receptor for MANF and regulator of neuronal survival.
Original languageEnglish
Article number112066
JournalCell Reports
Issue number2
Number of pages31
Publication statusPublished - 28 Feb 2023
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3112 Neurosciences
  • Endoplasmic-reticulum stress
  • Unfolded protein response
  • Neurotrophic factor
  • Transmembrane protein
  • Kappa-b
  • Beta
  • Activation
  • Model
  • Proliferation
  • Homeostasis

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