ZUFSP Deubiquitylates K63-Linked Polyubiquitin Chains to Promote Genome Stability
ZUFSP Deubiquitylates K63-Linked Polyubiquitin Chains to Promote Genome Stability
复制标题
DOI：
10.1016/j.molcel.2018.02.024
复制
发表时间：
2018-04-05
期刊：
影响因子：
16
通讯作者：
Mailand, Niels
中科院分区：
文献类型：
--
作者：
Haahr, Peter;Borgermann, Nikoline;Mailand, Niels
去泛素化酶（DUBs）通过在多个水平上逆转和调节细胞泛素化过程来增强多功能泛素（Ub）密码的动力学。在这里，我们发现，未表征的人类蛋白ZUFSP（锌指与UFM 1特异性肽酶结构域蛋白/C6 orf 113/ZUP 1），这已被注释为一个潜在的失活UFM 1蛋白酶，和它的裂殖酵母同源物Mug 105定义了一个以前未被识别的进化保守的半胱氨酸蛋白酶DUBs类。人ZUFSP通过串联的Ub结合结构域选择性地与K63连接的多聚Ub长链相互作用并切割，而它对单Ub或二Ub底物显示出较差的活性。在细胞中，ZUFSP被募集到基因毒性应激位点并调节K63-Ub缀合物，以依赖于其催化活性的方式在复制应激时促进染色体稳定性。我们的研究结果确立了ZUFSP作为一种新型的连接选择性半胱氨酸肽酶DUB，在基因组维持途径中发挥作用。
Deubiquitylating enzymes (DUBs) enhance the dynamics of the versatile ubiquitin (Ub) code by reversing and regulating cellular ubiquitylation processes at multiple levels. Here we discovered that the uncharacterized human protein ZUFSP (zinc finger with UFM1-specific peptidase domain protein/C6orf113/ZUP1), which has been annotated as a potentially inactive UFM1 protease, and its fission yeast homolog Mug105 define a previously unrecognized class of evolutionarily conserved cysteine protease DUBs. Human ZUFSP selectively interacts with and cleaves long K63-linked poly-Ub chains by means of tandem Ub-binding domains, whereas it displays poor activity toward mono- or di-Ub substrates. In cells, ZUFSP is recruited to and regulates K63-Ub conjugates at genotoxic stress sites, promoting chromosome stability upon replication stress in a manner dependent on its catalytic activity. Our findings establish ZUFSP as a new type of linkage-selective cysteine peptidase DUB with a role in genome maintenance pathways.