Eukaryotic cells perform a range of complex processes, some essential for life, others specific to cell type, all of which are governed by post-translational modifications of proteins. Among the repertoire of dynamic protein modifications, ubiquitination is arguably the most arcane and profound due to its complexity. Ubiquitin conjugation consists of three main steps, the last of which involves a multitude of target-specific ubiquitin ligases that conjugate a range of ubiquitination patterns to protein substrates with diverse outcomes. In contrast, ubiquitin removal is catalysed by a relatively small number of de-ubiquitinating enzymes (DUBs), which can also display target specificity and impact decisively on cell function. Here we review the current knowledge of the intriguing ubiquitin-specific protease 17 (USP17) family of DUBs, which are expressed from a highly copy number variable gene that has been implicated in multiple cancers, although available evidence points to conflicting roles in cell proliferation and survival. We show that key USP17 substrates populate two pathways that drive cell cycle progression and that USP17 activity serves to promote one pathway but inhibit the other. We propose that this arrangement enables USP17 to stimulate or inhibit proliferation depending on the mitogenic pathway that predominates in any given cell and may partially explain evidence pointing to both oncogenic and tumour suppressor properties of USP17.

真核细胞执行一系列复杂的过程，有些是生命所必需的，有些是特定于细胞类型的，所有这些都由蛋白质的翻译后修饰控制。在动态蛋白质修饰的全部内容中，泛素化可以说是最神秘和最深刻的，因为它的复杂性。泛素偶联包括三个主要步骤，最后一个步骤涉及多种靶标特异性泛素连接酶，这些连接酶将一系列泛素化模式与具有不同结果的蛋白质底物偶联。相比之下，泛素的去除是由数量相对较少的去泛素化酶 (DUB) 催化的，DUB 也可以显示目标特异性并对细胞功能产生决定性影响。在这里，我们回顾了有关 DUB 的有趣的泛素特异性蛋白酶 17 (USP17) 家族的当前知识，它们由与多种癌症有关的高拷贝数可变基因表达，尽管现有证据表明在细胞增殖和存活中的作用相互矛盾。我们表明，关键的 USP17 底物填充了驱动细胞周期进程的两种途径，并且 USP17 活性有助于促进一种途径但抑制另一种途径。我们建议这种安排使 USP17 能够根据在任何给定细胞中占主导地位的有丝分裂途径刺激或抑制增殖，并且可以部分解释指向 USP17 致癌和肿瘤抑制特性的证据。我们表明，关键的 USP17 底物填充了驱动细胞周期进程的两种途径，并且 USP17 活性有助于促进一种途径但抑制另一种途径。我们建议这种安排使 USP17 能够根据在任何给定细胞中占主导地位的有丝分裂途径刺激或抑制增殖，并且可以部分解释指向 USP17 致癌和肿瘤抑制特性的证据。我们表明，关键的 USP17 底物填充了驱动细胞周期进程的两种途径，并且 USP17 活性有助于促进一种途径但抑制另一种途径。我们建议这种安排使 USP17 能够根据在任何给定细胞中占主导地位的有丝分裂途径刺激或抑制增殖，并且可以部分解释指向 USP17 致癌和肿瘤抑制特性的证据。