A Role for the Unfolded Protein Response in Optimizing Antibody Secretion

Mol Immunol. 2004 Jul;41(9):919-27. doi: 10.1016/j.molimm.2004.04.023.

Abstract

Terminal differentiation of B lymphocytes into antibody(Ab)-secreting plasma cells is marked by a sharp rise in immunoglobulin (Ig) biosynthesis that increases demand on the protein folding capacity of the endoplasmic reticulum (ER). The unfolded protein response pathway (UPR) allows cells to respond to challenging conditions within the ER, in part by the activities of the XBP1 and ATF6alpha/beta transcription factors. The UPR is activated in differentiating B cells, and XBP1 is required for the generation of Ab-secreting plasma cells. Therefore, it has been hypothesized that the UPR mediates ER homeostasis as B cells transition into high-rate Ab secretion. We sought to test this hypothesis in primary murine splenic B cells stimulated to secrete Ab in vitro. Here, we report that enforced expression of a dominant-negative ATF6alpha mutant in differentiating B cells reduces the output of secreted IgM and increases improper release of IgM assembly intermediates. These data indicate that the UPR functions to optimize the efficiency of Ab secretion and provide new insight into the fundamental role of the UPR in humoral immunity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activating Transcription Factor 6
  • Animals
  • Antibody Formation / immunology*
  • Antibody Formation / physiology
  • Antigens / immunology*
  • Cell Differentiation / immunology
  • Cell Differentiation / physiology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression Regulation / physiology
  • Genes, Dominant / physiology
  • Mice
  • Mutation
  • Plasma Cells / immunology
  • Plasma Cells / physiology
  • Protein Denaturation / immunology
  • Proteins / immunology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Activating Transcription Factor 6
  • Antigens
  • Atf6 protein, mouse
  • DNA-Binding Proteins
  • Proteins
  • Transcription Factors