Kisselev Alexei F, Groettrup Marcus
Department of Pharmacology & Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH 03756, USA.
Division of Immunology, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany; Biotechnology Institute Thurgau (BITg) at the University of Konstanz, CH-8280 Kreuzlingen, Switzerland.
Curr Opin Chem Biol. 2014 Dec;23:16-22. doi: 10.1016/j.cbpa.2014.08.012. Epub 2014 Sep 15.
Specialized variants of the constitutive 20S proteasome in the immune system like the immunoproteasomes and the thymoproteasome contain active site-bearing subunits which differ in their cleavage priorities and substrate binding pockets. The immunoproteasome plays a crucial role in antigen processing and for the differentiation of pro-inflammatory T helper cells which are involved in the pathogenesis of autoimmunity. Selective inhibitors of the immunoproteasome and constitutive proteasome have recently been generated which interfere with the development and progression of autoimmune diseases. Here we describe these inhibitors and their therapeutic potential as predicted from preclinical models.
免疫系统中组成型20S蛋白酶体的特殊变体，如免疫蛋白酶体和胸腺蛋白酶体，包含具有活性位点的亚基，这些亚基在切割优先级和底物结合口袋方面存在差异。免疫蛋白酶体在抗原加工以及参与自身免疫发病机制的促炎性辅助性T细胞的分化中起关键作用。最近已经产生了免疫蛋白酶体和组成型蛋白酶体的选择性抑制剂，它们会干扰自身免疫性疾病的发展和进程。在此，我们描述这些抑制剂及其从临床前模型预测的治疗潜力。
