USP2 is an SKP2 deubiquitylase that stabilizes both SKP2 and its substrates.
USP2 is an SKP2 deubiquitylase that stabilizes both SKP2 and its substrates.
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USP2 是一种 SKP2 去泛素化酶，可稳定 SKP2 及其底物。
DOI：
10.1016/j.jbc.2021.101109
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Zhang F;Zhao Y;Sun Y
蛋白质的稳定性受其泛素化和去泛素化之间的平衡调节。S期激酶相关蛋白2（SKP 2）是一种致癌的F-box蛋白，其识别肿瘤抑制底物，用于通过E3连接酶SKP 1-Cullin 1-F-box靶向泛素化和通过蛋白酶体降解。SKP 2本身被E3连接酶APC/CCDH 1和SCFFBXW 2泛素化，并被去泛素化酶（DUB）USP 10和USP 13去泛素化。考虑到SKP 2的生物学意义，其他E3或DUB也可能调节其稳定性。在这里，我们报告了USP 2作为新DUB的鉴定和表征。我们首先筛选了一组DUB，发现USP 2和USP 21都与内源性SKP 2结合，但只有USP 2去泛素化并稳定SKP 2蛋白。通过siRNA敲低或小分子抑制剂处理的USP 2失活通过增强其泛素化和随后的降解显著缩短SKP 2蛋白半衰期。出乎意料的是，USP 2稳定的SKP 2不会使其底物p21和p27不稳定。从机制上讲，USP 2通过SKP 2上富含亮氨酸的重复底物结合结构域与SKP 2结合，以破坏SKP 2-底物结合，从而使SKP 2和这些底物稳定。在生物学上，由USP 2敲低或USP 2抑制剂诱导的生长抑制部分通过调节SKP 2及其底物介导。我们的研究揭示了E3-DUB底物之间串扰的新机制及其在靶向USP 2-SKP 2轴用于癌症治疗中的潜在意义。
The stability of a protein is regulated by a balance between its ubiquitylation and deubiquitylation. S-phase kinase-associated protein 2 (SKP2) is an oncogenic F-box protein that recognizes tumor suppressor substrates for targeted ubiquitylation by the E3 ligase SKP1-Cullin1-F-box and degradation by proteasome. SKP2 is itself ubiquitylated by the E3 ligases APC/CCDH1 and SCFFBXW2, and deubiquitylated by deubiquitylases (DUBs) USP10 and USP13. Given the biological significance of SKP2, it is likely that the other E3s or DUBs may also regulate its stability. Here, we report the identification and characterization of USP2 as a new DUB. We first screened a panel of DUBs and found that both USP2 and USP21 bound to endogenous SKP2, but only USP2 deubiquitylated and stabilized SKP2 protein. USP2 inactivation via siRNA knockdown or small-molecule inhibitor treatment remarkably shortened SKP2 protein half-life by enhancing its ubiquitylation and subsequent degradation. Unexpectedly, USP2-stabilized SKP2 did not destabilize its substrates p21 and p27. Mechanistically, USP2 bound to SKP2 via the leucine-rich repeat substrate-binding domain on SKP2 to disrupt the SKP2-substrate binding, leading to stabilization of both SKP2 and these substrates. Biologically, growth suppression induced by USP2 knockdown or USP2 inhibitor is partially mediated via modulation of SKP2 and its substrates. Our study revealed a new mechanism of the cross-talk among the E3–DUB substrates and its potential implication in targeting the USP2–SKP2 axis for cancer therapy.
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影响因子：
11.8
作者：
Nakayama, K;Nagahama, H;Nakayama, KI
通讯作者：
Nakayama, KI
影响因子：
14.5
作者：
Cai, Zhen;Moten, Asad;Peng, Danni;Hsu, Che-Chia;Pan, Bo-Syong;Manne, Rajeshkumar;Li, Hong-yu;Lin, Hui-Kuan
通讯作者：
Lin, Hui-Kuan
DOI：
10.1073/pnas.0406789102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Huang, H;Regan, KM;Tindall, DJ
通讯作者：
Tindall, DJ
DOI：
10.1073/pnas.1100028108
发表时间：
2011-05-31
影响因子：
11.1
作者：
Chen, Meifan;Gutierrez, Gustavo J.;Ronai, Ze'ev A.
通讯作者：
Ronai, Ze'ev A.
USP10 通过稳定慢性粒细胞白血病中的 SKP2 来调节 SKP2/Bcr-Abl 轴
影响因子：
33.5
作者：
Liao, Yuning;Liu, Ningning;Liu, Jinbao
通讯作者：
Liu, Jinbao