Regulation of USP28 de-ubiquitinating activity by SUMO conjugation [Protein Synthesis and Degradation]

October 30th, 2014 by Zhen, Y., Knobel, P. A., Stracker, T. H., Reverter, D.

Ubiquitin-Specific Protease 28 (USP28) is a deubiquitinating enzyme that has been implicated in the DNA damage response (DDR), 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 de-ubiquitinating activity on di-ubiquitin or poly-ubiquitin chain substrates. In contrast to other characterized USP de-ubiquitinases, our results indicate that USP28 has a chain preference activity for K11, K48 and K63 di-ubiquitin linkages.