Zhen Yang, Knobel Philip A, Stracker Travis H, Reverter David
From the Institut de Biotecnologia i de Biomedicina and Departament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain and.
the Institute for Research in Biomedicine, 08028 Barcelona, Spain.
J Biol Chem. 2014 Dec 12;289(50):34838-50. doi: 10.1074/jbc.M114.601849. Epub 2014 Oct 30.
USP28 (ubiquitin-specific protease 28) is a deubiquitinating enzyme that has been implicated in the DNA damage response, the regulation of Myc signaling, and cancer progression. The half-life stability of major regulators of critical cellular pathways depends on the activities of specific ubiquitin E3 ligases that target them for proteosomal degradation and deubiquitinating enzymes that promote their stabilization. One function of the post-translational small ubiquitin modifier (SUMO) is the regulation of enzymatic activity of protein targets. In this work, we demonstrate that the SUMO modification of the N-terminal domain of USP28 negatively regulates its deubiquitinating activity, revealing a role for the N-terminal region as a regulatory module in the control of USP28 activity. Despite the presence of ubiquitin-binding domains in the N-terminal domain, its truncation does not impair deubiquitinating activity on diubiquitin or polyubiquitin chain substrates. In contrast to other characterized USP deubiquitinases, our results indicate that USP28 has a chain preference activity for Lys(11), Lys(48), and Lys(63) diubiquitin linkages.
USP28（泛素特异性蛋白酶28）是一种去泛素化酶，与DNA损伤反应、Myc信号调控及癌症进展有关。关键细胞通路主要调节因子的半衰期稳定性取决于特定泛素E3连接酶的活性，这些连接酶将它们靶向蛋白酶体降解，而去泛素化酶则促进它们的稳定。翻译后小泛素修饰物（SUMO）的一个功能是调节蛋白质靶标的酶活性。在这项研究中，我们证明USP28 N端结构域的SUMO修饰负向调节其去泛素化活性，揭示了N端区域作为USP28活性控制中的一个调节模块的作用。尽管N端结构域存在泛素结合结构域，但其截短并不损害对双泛素或多泛素链底物的去泛素化活性。与其他已表征的USP去泛素化酶不同，我们的结果表明USP28对Lys(11)、Lys(48)和Lys(63)双泛素连接具有链偏好活性。
