Expression of endoplasmic reticulum (ER) resident molecular chaperones increases when activation B lymphocytes differentiate into high-rate antibody-secreting cells. These chaperones facilitate the proper folding of proteins, including immunoglobulins, in the ER. Therefore, elevated chaperone levels and overall expansion of the ER during B-cell differentiation are likely critical for effective antibody responses. Increased levels of ER chaperones may provide a protective advantage to neoplastic cells, thereby facilitating tumor progression. This coupled with the fact that a variety of disorders including the most common form of cystic fibrosis originate due to aberrant protein folding in the ER underscore the need to understand mechanisms that regulate expression of ER chaperones. The long-term objective of this application is to elucidate the signaling mechanism that controls ER homeostasis in differentiating B-cells. Using the CH12 B-cell line that differentiates in response to defined stimuli, the timing of the induction of ER chaperone expression during B-cell differentiation will be determined. Second, the unfolded protein response (UPR) signaling pathway will be examined in differentiating B-cells. The UPR leads to up-regulated synthesis of ER chaperones when unfolded proteins accumulate in the ER. Third, the role of ER transmembrane signaling proteins (Ern1 and 2) in regulating ER chaperone expression during B-cell differentiation will be investigated. The Ern proteins serve as proximal components of the UPR pathway. Ern mutants will be introduced into B-cells and monitored for their effect on up-regulated synthesis of ER chaperones during differentiation.
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