免疫系统
硼替佐米
蛋白酶体
蛋白酶体抑制剂
化学
活力测定
细胞毒性T细胞
异种移植
程序性细胞死亡
细胞
癌症研究
细胞生物学
免疫学
生物
细胞凋亡
移植
生物化学
体外
医学
外科
多发性骨髓瘤
作者
Ena Ladi,Christine Everett,Craig E. Stivala,Blake E. Daniels,Matthew R. Durk,Seth F. Harris,Malcolm P. Huestis,Hans E. Purkey,Steven T. Staben,Martin Augustin,M. Blaesse,S. Steinbacher,Céline Eidenschenk,Rajita Pappu,Michael Siu
标识
DOI:10.1021/acs.jmedchem.9b00509
摘要
The pan-proteasome inhibitor bortezomib demonstrated clinical efficacy in off-label trials of Systemic Lupus Erythematosus. One potential mechanism of this clinical benefit is from the depletion of pathogenic immune cells (plasmablasts and plasmacytoid dendritic cells). However, bortezomib is cytotoxic against nonimmune cells, which limits its use for autoimmune diseases. An attractive alternative is to selectively inhibit the immune cell-specific immunoproteasome to deplete pathogenic immune cells and spare nonhematopoietic cells. Here, we disclose the development of highly subunit-selective immunoproteasome inhibitors using insights obtained from the first bona fide human immunoproteasome cocrystal structures. Evaluation of these inhibitors revealed that immunoproteasome-specific inhibition does not lead to immune cell death as anticipated and that targeting viability requires inhibition of both immuno- and constitutive proteasomes. CRISPR/Cas9-mediated knockout experiments confirmed upregulation of the constitutive proteasome upon disruption of the immunoproteasome, protecting cells from death. Thus, immunoproteasome inhibition alone is not a suitable approach to deplete immune cells.
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