Understanding Human Deubiquitinases Target Specificity by Network-based Analysis towards their Development as Therapeutics Target

Abstract

Deubiquitinases (DUBs), a component of protein ubiquitination, regulate many biological processes and cellular pathways critical for cell survival, proliferation, genome stability and transcriptional control that are closely related to disease such as cancer. DUBs rely on their interaction with target proteins in order to function within a particular pathway. However, there is currently little information on the DUBs' target protein. To observe the target distribution and specificity of the seven DUBs family (USP, UCH, MJD, OTU, JAMM, MINDY, ZUFSP), protein partners of every member in DUBs family were extracted from IntAct, MINT and IMEx databases and protein-protein interaction (PPI) network was constructed and analysed in Cytoscape, an open source software platform for visualising molecular interaction network. The PPI network of DUBs consists of 2328 nodes and 3409 edges and follows a power law distribution that corresponds to scale-free topology. From the PPI network, DUBs interaction is divided into: (1) DUBs-ubiquitin enzymes (e.g. E2 conjugating enzyme and E3 ligase), (2) DUBs-DUBs or also known as 'DUBbing DUBs' and (3) DUBs-other target proteins. We observed that only approximately 60% of proteins were the unique targets of each DUBs family, suggesting that target preference may not be conferred according to DUBs family as in the case of ubiquitin-linkage preference. Utilising the information from this study, it is anticipated that the potential of DUBs as diseases therapeutics target could be fully explored.