The Ubiquitin Tale: Current Strategies and Future Challenges.

Ubiquitin (Ub) is often considered a structurally conserved protein. Ubiquitination plays a prominent role in the regulation of physiological pathways. Since the first mention of Ub in protein degradation pathways, a plethora of nonproteolytic functions of this post-translational modification have been identified and investigated in detail. In addition, several other structurally and functionally related proteins have been identified and investigated for their Ub-like structures and functions. Ubiquitination and Ub-like modifications play vital roles in modulating the pathways involved in crucial biological processes and thus affect the global proteome. In this Review, we provide a snapshot of pathways, substrates, diseases, and novel therapeutic targets that are associated with ubiquitination or Ub-like modifications. In the past few years, a large number of proteomic studies have identified pools of ubiquitinated proteins (ubiquitylomes) involved or induced in healthy or stressed conditions. These comprehensive studies involving identification of new ubiquitination substrates and sites contribute enormously to our understanding of ubiquitination in more depth. However, with the current tools, there are certain limitations that need to be addressed. We review recent technological advancements in ubiquitylomic studies and their limitations and challenges. Overall, large-scale ubiquitylomic studies contribute toward understanding global ubiquitination in the contexts of normal and disease conditions.