ER Stress: UPR

• ER stress and type 2 diabetes

  • pre-diabetes -> higher blood glucose -> beta cells in pancreas work harder to produce more insulin
  • diabetes -> beta cells can't sustain a high level of insulin due to ER workload -> very high blood glucose

  
• in ER stress there are 3 key sensor proteins

  • PERK
  • IRE1a
  • ATF6a
• ER stress sensor protein: PERK

  • normal protein -> BiP binds to PERK -> transmembrane kinase PERK is off
  • unfolded protein binds to BiP -> unbound PERK has exposed lumen domain and homodimerizes -> auto phosphorylation on cytoplasmic side -> homodimer PERK phosphorylates EF2 -> EF2 destabilizes general mRNA translation and upregulates specific mRNA translation like ATF4 protein TF which transits to the nucleus to target genes like
  • ERAD quality control
  • chaperones and foldases
  • metabolism and redox for ROS

  
• ER stress sensor protein: IRE1

  • normal protein -> BiP binds to IRE1 -> IRE1 off
  • unfolded protein binds to BiP -> unbound IRE1 has exposed lumen domain and homodimerizes -> auto phosphorylation on cytoplasmic side -> IRE1 turns on/phosphorylates an RNase which splices Xbp1 mRNA to remove hairpin loop and express mRNA into Xbp1 protien to be TF for target genes like
  • chaperones and foldases
  • ERAD quality control
  • ER biogenesis
  • secretory machinery

  
• ER stress sensor protein: ATF6

  • normal protein -> BiP binds to ATF6 -> off, this keeps ATF6 in the ER (BiP = golgi transport translocation inhibitor for ATF6)
  • unfolded protein binds to BiP -> ATF6 transits to golgi -> ATF6 processed through 2 proteolytic sites that release the N terminus cytoplasmic fragment to transit to the nucleus as TF for target genes like
  • chaperones and foldases
  • ERAD quality control
  • ER biogenesis
  • secretory machinery

  
• BiP is an ER resident chaperone protein that binds to unfolded proteins to help them fold

  • cells have lots of BiP and some are bound to unfolded protein response (UPR) sensors
  • if buildup of unfolded proteins in ER -> BiP dissociates from UPR sensors which activates the UPR

  
• the unfolded protein response (UPR) is triggered by a buildup of unfolded proteins in the ER caused by

  • chemical damage to proteins
  • protein overproduction beyond ER workload capacity
  • pathological conditions that affect protein folding
• sensing of unfolded proteins result in

  • PERK phosphorylation -> inhibit general protein translation
  • IRE1 phosphorylation -> increase chaperone protein translation
  • ATF6 ER membrane dissociation -> be TF for target genes to help deal with ER stress