Activation of an unfolded protein response during differentiation of antibody-secreting B cells.
The unfolded protein response pathway (UPR) is believed to detect and compensate for excessive protein accumulation in the endoplasmic reticulum (ER). The UPR can be induced by pharmacological agents that perturb ER functions, but may also occur during cellular developmental processes such as the transition of B-lymphocytes into antibody-secreting plasma cells. Here we show that major UPR components are activated in B cells stimulated to secrete antibody. Increased expression of UPR targets including the ER chaperones BiP and GRP94 and the transcription factor XBP-1 initiates early in the differentiation program prior to up-regulated synthesis of Ig chains. Furthermore, these same kinetics are observed during differentiation for cleavage of the ER-localized ATF6alpha protein and splicing of XBP-1 mRNA to generate p50ATF6alpha and p54XBP-1, the two known UPR transcriptional activators. All of these UPR events reach maximal levels once Ig synthesis and secretion are markedly induced. Interestingly, these events are not accompanied by expression of CHOP, a transcription factor induced by ER stress agents commonly used to investigate the UPR. These results suggest that a physiological UPR elicited during differentiation of B-lymphocytes into high-rate secretory cells may be distinct from the UPR defined by agents that disrupt protein maturation in the ER.
Gass
Jennifer N
JN
Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, USA.
Gifford
Nicole M
NM
Brewer
Joseph W
JW
D000906:Antibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D018832:Molecular Chaperones / Q000096:biosynthesis; D011489:Protein Denaturation; D000071701:Regulatory Factor X Transcription Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000906:Antibodies; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D018832:Molecular Chaperones; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D051742:Transcription Factor CHOP