The proteasome is a well-identified therapeutic target for cancer treatment. It acts as the main protein degradation system in the cell and degrades key mediators of cell growth, survival and function. The term “proteasome” embraces a whole family of distinct complexes, which share a common proteolytic core, the 20S proteasome, but differ by their attached proteasome activators. Each of these proteasome complexes plays specific roles in the control of cellular function. In addition, distinct proteasome interacting proteins regulate proteasome activity in subcellular compartments and in response to cellular signals. Proteasome activators and regulators may thus serve as building blocks to fine-tune proteasome function in the cell according to cellular needs.

Inhibitors of the proteasome, e.g. the FDA approved drugs Velcade™, Kyprolis™, Ninlaro™, inactivate the catalytic 20S core and effectively block protein degradation of all proteasome complexes in the cell resulting in inhibition of cell growth and induction of apoptosis. Efficacy of these inhibitors, however, is hampered by their pronounced cytotoxic side-effects as well as by the emerging development of resistance to catalytic proteasome inhibitors. Targeted inhibition of distinct buiding blocks of the proteasome system, i.e. proteasome activators or regulators, represents an alternative strategy to overcome these limitations.

In this review, we stress the importance of the diversity of the proteasome complexes constituting an entire proteasome system. Our building block concept provides a rationale for the defined targeting of distinct proteasome super-complexes in disease. We thereby aim to stimulate the development of innovative therapeutic approaches beyond broad catalytic proteasome inhibition.

蛋白酶体是癌症治疗的公认靶标。它充当细胞中主要的蛋白质降解系统，并降解细胞生长，存活和功能的关键介体。术语“蛋白酶体”包括一整套独特的复合物，它们共享一个共同的蛋白水解核心，即20S蛋白酶体，但它们所连接的蛋白酶体激活剂不同。这些蛋白酶体复合物中的每一种都在控制细胞功能中起特定作用。另外，不同的蛋白酶体相互作用蛋白调节亚细胞区室中和响应细胞信号的蛋白酶体活性。蛋白酶体激活剂和调节剂因此可以用作构建基块，以根据细胞需求微调细胞中的蛋白酶体功能。

蛋白酶体的抑制剂，例如FDA批准的Velcade™，Kyprolis™，Ninlaro™药物，可以使20S催化核心失活，并有效阻断细胞中所有蛋白酶体复合物的蛋白质降解，从而抑制细胞生长并诱导凋亡。然而，这些抑制剂的功效因其明显的细胞毒性副作用以及对催化蛋白酶体抑制剂的抗药性的发展而受到阻碍。有针对性地抑制蛋白酶体系统不同的结构模块，即蛋白酶体激活剂或调节剂，代表了克服这些局限性的替代策略。

在这篇综述中，我们强调了构成整个蛋白酶体系统的蛋白酶体复合物多样性的重要性。我们的构件概念为疾病中不同蛋白酶体超复合物的明确靶向提供了依据。因此，我们旨在刺激广泛的催化蛋白酶体抑制作用之外的创新治疗方法的发展。