Rapid B cell receptor-induced unfolded protein response in nonsecretory B cells correlates with pro- versus antiapoptotic cell fate.
The adaptive unfolded protein response (UPR) is essential for the development of antibody-secreting plasma cells. B cells induced by lipopolysaccharide (LPS) to differentiate into plasma cells exhibit a nonclassical UPR reported to anticipate endoplasmic reticulum stress prior to immunoglobulin production. Here we demonstrate that activation of a physiologic UPR is not limited to cells undergoing secretory cell differentiation. We identify B cell receptor (BCR) signaling as an unexpected physiologic UPR trigger and demonstrate that in mature B cells, BCR stimulation induces a short lived UPR similar to the LPS-triggered nonclassical UPR. However, unlike LPS, BCR stimulation does not induce plasma cell differentiation. Furthermore, the BCR-induced UPR is not limited to cells in which BCR induces activation, since a UPR is also induced in transitional immature B cells that respond to BCR stimulation with a rapid apoptotic fate. This response involves sustained up-regulation of Chop mRNA indicative of a terminal UPR. Whereas sustained Chop expression correlates with the ultimate fate of the BCR-triggered B cell and not its developmental stage, Chop-/- B cells undergo apoptosis, indicating that CHOP is not required for this process. These studies establish a system whereby a terminal or adaptive UPR can be alternatively triggered by physiologic stimuli.
Skalet
Alison H
AH
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Isler
Jennifer A
JA
King
Leslie B
LB
Harding
Heather P
HP
Ron
David
D
Monroe
John G
JG
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D019013:CD40 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation; D019070:Cell Lineage; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005091:Exons; D017930:Genes, Reporter; D007136:Immunoglobulins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009154:Mutation; D011489:Protein Denaturation; D017510:Protein Folding; D012333:RNA, Messenger / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism; D015854:Up-Regulation
D019013:CD40 Antigens; C497250:Ddit3 protein, mouse; D007136:Immunoglobulins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D019948:Receptors, Interleukin-4; D051197:Toll-Like Receptor 4; D051742:Transcription Factor CHOP