Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity

J Clin Invest. 2015 May;125(5):1955-67. doi: 10.1172/JCI78863. Epub 2015 Apr 6.

Abstract

The HSP40 cochaperone SEC63 is associated with the SEC61 translocon complex in the ER. Mutations in the gene encoding SEC63 cause polycystic liver disease in humans; however, it is not clear how altered SEC63 influences disease manifestations. In mice, loss of SEC63 induces cyst formation both in liver and kidney as the result of reduced polycystin-1 (PC1). Here we report that inactivation of SEC63 induces an unfolded protein response (UPR) pathway that is protective against cyst formation. Specifically, using murine genetic models, we determined that SEC63 deficiency selectively activates the IRE1α-XBP1 branch of UPR and that SEC63 exists in a complex with PC1. Concomitant inactivation of both SEC63 and XBP1 exacerbated the polycystic kidney phenotype in mice by markedly suppressing cleavage at the G protein-coupled receptor proteolysis site (GPS) in PC1. Enforced expression of spliced XBP1 (XBP1s) enhanced GPS cleavage of PC1 in SEC63-deficient cells, and XBP1 overexpression in vivo ameliorated cystic disease in a murine model with reduced PC1 function that is unrelated to SEC63 inactivation. Collectively, the findings show that SEC63 function regulates IRE1α/XBP1 activation, SEC63 and XBP1 are required for GPS cleavage and maturation of PC1, and activation of XBP1 can protect against polycystic disease in the setting of impaired biogenesis of PC1.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • DNA Helicases / deficiency
  • DNA Helicases / genetics
  • DNA Helicases / physiology*
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Disease Models, Animal
  • Endoribonucleases / metabolism*
  • Female
  • Glucosidases / deficiency
  • Glucosidases / genetics
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Kidney / metabolism
  • Kidney / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Chaperones
  • Polycystic Kidney, Autosomal Dominant / genetics*
  • Polycystic Kidney, Autosomal Dominant / metabolism
  • Polycystic Kidney, Autosomal Recessive / genetics*
  • Polycystic Kidney, Autosomal Recessive / metabolism
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Splicing
  • RNA, Small Interfering / genetics
  • RNA-Binding Proteins
  • Receptors, G-Protein-Coupled / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Regulatory Factor X Transcription Factors
  • TRPP Cation Channels / biosynthesis
  • TRPP Cation Channels / deficiency*
  • TRPP Cation Channels / genetics
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Transfection
  • Unfolded Protein Response / physiology*
  • X-Box Binding Protein 1

Substances

  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • Prkcsh protein, mouse
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Receptors, G-Protein-Coupled
  • Recombinant Fusion Proteins
  • Regulatory Factor X Transcription Factors
  • SEC63 protein, mouse
  • TRPP Cation Channels
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, mouse
  • polycystic kidney disease 1 protein
  • Ern1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • Glucosidases
  • DNA Helicases