A role for the unfolded protein response in optimizing antibody secretion.
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.
Gunn
Kathryn E
KE
Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago 2160 South First Avenue, Maywood, IL 60153, USA.
Gifford
Nicole M
NM
Mori
Kazutoshi
K
Brewer
Joseph W
JW
D051702:Activating Transcription Factor 6; D000818:Animals; D000917:Antibody Formation / Q000276:immunology* / Q000502:physiology; D000941:Antigens / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D005799:Genes, Dominant / Q000502:physiology; D051379:Mice; D009154:Mutation; D010950:Plasma Cells / Q000276:immunology / Q000502:physiology; D011489:Protein Denaturation / Q000276:immunology; D011506:Proteins / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D051702:Activating Transcription Factor 6; D000941:Antigens; C497112:Atf6 protein, mouse; D004268:DNA-Binding Proteins; D011506:Proteins; D014157:Transcription Factors