Gass Jennifer N, Gifford Nicole M, Brewer Joseph W
Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, USA.
J Biol Chem. 2002 Dec 13;277(50):49047-54. doi: 10.1074/jbc.M205011200. Epub 2002 Oct 8.
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.
未折叠蛋白反应途径（UPR）被认为可检测并补偿内质网（ER）中过量的蛋白质积累。UPR可由干扰ER功能的药物诱导，但也可能发生在细胞发育过程中，如B淋巴细胞向分泌抗体的浆细胞转变期间。在此我们表明，主要的UPR组分在被刺激分泌抗体的B细胞中被激活。包括ER伴侣蛋白BiP和GRP94以及转录因子XBP-1在内的UPR靶标的表达增加，在Ig链合成上调之前就已在分化程序的早期启动。此外，在分化过程中，对于ER定位的ATF6α蛋白的切割以及XBP-1 mRNA的剪接以产生两种已知的UPR转录激活因子p50ATF6α和p54XBP-1，也观察到了相同的动力学。一旦Ig合成和分泌被显著诱导，所有这些UPR事件都达到最高水平。有趣的是，这些事件并未伴随着CHOP的表达，CHOP是一种由常用于研究UPR的ER应激剂诱导的转录因子。这些结果表明，在B淋巴细胞分化为高速分泌细胞过程中引发的生理性UPR可能与由破坏ER中蛋白质成熟的试剂所定义的UPR不同。
