Division of Genetics and Cell Biology, DiBiT, San Raffaele Scientific Institute, and Università Vita-Salute San Raffaele, Milano, Italy.
Semin Hematol. 2012 Jul;49(3):215-22. doi: 10.1053/j.seminhematol.2012.04.005.
The ability of eukaryotic cells to adapt to changing environmental conditions, respond to stimuli, and differentiate relies on their capacity to control the concentration, conformation, localization, and interaction of proteins, thereby reshaping their proteome. Protein degradation plays a critical role in maintaining protein homeostasis, and hence is carefully regulated. During the spectacular and demanding metamorphosis of activated B lymphocytes, expression programs are launched in coordinated waves, and adaptive strategies are deployed to prepare for antibody secretion. Surprisingly, though, despite increased demand for proteolysis, proteasome capacity collapses. As a result, antibody-secreting cells show symptoms of proteotoxic stress, and become extremely vulnerable to proteasome inhibition. The emerging concept that proteostenosis naturally follows B-cell activation has biological and immune implications, for it provides a model to dissect the integrated regulation of protein homeostasis, and a molecular counter limiting antibody responses, of use against autoimmune diseases. Mounting evidence linking proteotoxicity with proteasome vulnerability in malignant plasma cells visualizes strategies to understand responsiveness and obviate resistance to proteasome inhibition, with implications for the biology and therapy of plasma cell dyscrasias, namely, light chain amyloidosis and multiple myeloma.
真核细胞适应环境变化、响应刺激和分化的能力依赖于其控制蛋白质浓度、构象、定位和相互作用的能力，从而重塑其蛋白质组。蛋白质降解在维持蛋白质平衡中起着关键作用，因此受到严格调控。在激活的 B 淋巴细胞的惊人而艰巨的变态过程中，表达程序以协调波的形式启动，并部署适应性策略为抗体分泌做准备。然而令人惊讶的是，尽管对蛋白酶体的需求增加，但蛋白酶体的能力却崩溃了。因此，分泌抗体的细胞表现出蛋白质毒性应激的症状，并且变得极易受到蛋白酶体抑制剂的影响。自然紧随 B 细胞激活的蛋白合成后抑制这一新兴概念具有生物学和免疫学意义，因为它为剖析蛋白质平衡的综合调控提供了一个模型，以及一种限制抗体反应的分子计数器，可用于治疗自身免疫性疾病。将蛋白毒性与恶性浆细胞中的蛋白酶体脆弱性联系起来的越来越多的证据，为理解响应性和避免对蛋白酶体抑制的耐药性提供了策略，这对浆细胞疾病的生物学和治疗具有重要意义，即轻链淀粉样变性和多发性骨髓瘤。
