Systems-Wide Analysis of Protein Ubiquitylation: We Finally Have the Tiger by the Tail

Ubiquitylation is a posttranslational modification in which ubiquitin, a conserved polypeptide, is conjugated to targeted proteins. The human genome encodes for over a thousand proteins that can either mediate ubiquitylation, remove the modification, or bind to modified proteins. Hence, the ubiquitin system is expected to affect a large portion of the proteome. Since its discovery, our understanding of the ubiquitin system has come a long way. Great efforts made by several prominent members of the scientific community have paid off, with leaps and bounds being made in areas such as the discovery of ubiquitylated proteins and ubiquitylation sites. Boosting the success of classical proteomic approaches, the recent introduction of a new method (by which ubiquitylated peptides are captured by antibodies) enabled the identification of a large number of ubiquitylation sites. In this chapter, we will review the different proteomic strategies that have been established in order to uncover which proteins are ubiquitylated in the cell, and then further discuss the novel biological insights revealed by these systems-wide studies.