文章：

PA28α下调诱导蛋白酶体重塑，导致多发性骨髓瘤对蛋白酶体抑制剂产生耐药

Downregulation of PA28α induces proteasome remodeling and results in resistance to proteasome inhibitors in multiple myeloma

原文发布日期：2020-12-14

DOI: 10.1038/s41408-020-00393-0

类型: Article

开放获取: 是

英文摘要：

Protein homeostasis is critical for maintaining eukaryotic cell function as well as responses to intrinsic and extrinsic stress. The proteasome is a major portion of the proteolytic machinery in mammalian cells and plays an important role in protein homeostasis. Multiple myeloma (MM) is a plasma cell malignancy with high production of immunoglobulins and is especially sensitive to treatments that impact protein catabolism. Therapeutic agents such as proteasome inhibitors have demonstrated significant benefit for myeloma patients in all treatment phases. Here, we demonstrate that the 11S proteasome activator PA28α is upregulated in MM cells and is key for myeloma cell growth and proliferation. PA28α also regulates MM cell sensitivity to proteasome inhibitors. Downregulation of PA28α inhibits both proteasomal load and activity, resulting in a change in protein homeostasis less dependent on the proteasome and leads to cell resistance to proteasome inhibitors. Thus, our findings suggest an important role of PA28α in MM biology, and also provides a new approach for targeting the ubiquitin-proteasome system and ultimately sensitivity to proteasome inhibitors.
 

摘要翻译： 

蛋白质稳态对于维持真核细胞功能以及应对内外源应激至关重要。蛋白酶体是哺乳动物细胞中蛋白水解机制的主要组成部分，在蛋白质稳态中发挥重要作用。多发性骨髓瘤是一种伴有免疫球蛋白大量产生的浆细胞恶性肿瘤，其对影响蛋白质分解代谢的治疗尤为敏感。蛋白酶体抑制剂等治疗药物在骨髓瘤患者的所有治疗阶段均显示出显著疗效。本文研究发现，11S蛋白酶体激活因子PA28α在多发性骨髓瘤细胞中表达上调，且对骨髓瘤细胞的生长和增殖至关重要。PA28α还调节多发性骨髓瘤细胞对蛋白酶体抑制剂的敏感性。下调PA28α可同时抑制蛋白酶体负荷和活性，导致蛋白质稳态转变为较少依赖蛋白酶体的状态，从而使细胞对蛋白酶体抑制剂产生耐药性。因此，我们的研究揭示了PA28α在多发性骨髓瘤生物学中的重要作用，并为靶向泛素-蛋白酶体系统及最终影响蛋白酶体抑制剂敏感性提供了新思路。

原文链接：

Downregulation of PA28α induces proteasome remodeling and results in resistance to proteasome inhibitors in multiple myeloma