A Molecular Mechanism for Turning Off IRE1α Signaling during Endoplasmic Reticulum Stress

Cell Rep. 2020 Dec 29;33(13):108563. doi: 10.1016/j.celrep.2020.108563.

Abstract

Misfolded proteins in the endoplasmic reticulum (ER) activate IRE1α endoribonuclease in mammalian cells, which mediates XBP1 mRNA splicing to produce an active transcription factor. This promotes the expression of specific genes to alleviate ER stress, thereby attenuating IRE1α. Although sustained activation of IRE1α is linked to human diseases, it is not clear how IRE1α is attenuated during ER stress. Here, we identify that Sec63 is a subunit of the previously identified IRE1α/Sec61 translocon complex. We find that Sec63 recruits and activates BiP ATPase through its luminal J-domain to bind onto IRE1α. This leads to inhibition of higher-order oligomerization and attenuation of IRE1α RNase activity during prolonged ER stress. In Sec63-deficient cells, IRE1α remains activated for a long period of time despite the presence of excess BiP in the ER. Thus, our data suggest that the Sec61 translocon bridges IRE1α with Sec63/BiP to regulate the dynamics of IRE1α signaling in cells.

Keywords: ER stress; IRE1; Sec61 translocon; endoplasmic reticulum; protein translocation; unfolded protein response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress*
  • Endoribonucleases / metabolism*
  • Gene Expression Regulation
  • Gene Knockout Techniques
  • HEK293 Cells
  • Heat-Shock Proteins / metabolism
  • Humans
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Models, Biological
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA Splicing
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • SEC Translocation Channels / genetics
  • SEC Translocation Channels / metabolism*
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Unfolded Protein Response*
  • X-Box Binding Protein 1 / genetics
  • X-Box Binding Protein 1 / metabolism*

Substances

  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins
  • Membrane Transport Proteins
  • Molecular Chaperones
  • RNA-Binding Proteins
  • SEC Translocation Channels
  • SEC62 protein, human
  • SEC63 protein, human
  • Transcription Factors
  • X-Box Binding Protein 1
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • Endoribonucleases