Ubiquitin Signaling: Chemistry Comes to the Rescue

Abstract

Posttranslational modification of proteins by ubiquitin (Ub), i.e., ubiquitination, mediates a variety of cellular processes, including protein homeostasis, cell cycle, DNA repair, and viral infections. Understanding the molecular mechanism of ubiquitination in these events is the basis for unraveling its precise role in health and disease. However, the inherent complexity of Ub signaling due to the high atomic complexity of Ub conjugates, where Ub is attached to other Ub molecules and to protein substrates in various forms, imposes a major challenge for these studies. In this regard, the enzymatic approaches employed for the preparation of important Ub conjugates have severe limitations to deliver them in high homogeneity and in adequate amounts for the desired study. Recent developments in the area of chemical synthesis and semisynthesis of proteins offer great solutions to the enzymatic limitations and enabling the preparation of various Ub conjugates with precise control over the atomic structure. These conjugates significantly contribute to deciphering Ub signaling at the molecular level, and with the synthetic tools in hand, chemical biologists have become key players in efforts toward understanding the complexity of the Ub code. In this Perspective, we highlight the key contributions of these synthetic approaches and how the development of novel Ub-based reagents is greatly assisting in uncovering unknown aspects of Ub signaling. We also discuss future aspirations to address unresolved questions in this exciting area of research.

Pleiotropic roles of the ubiquitin-proteasome system during viral propagation

“…The UPS can be manipulated by many viruses to facilitate viral replication, but the proteasome inhibitor MG132 can inhibit viral replication [20,46,47]. For example, the replication of some viruses such as human astrovirus [47], vaccinia virus [48], tombusvirus [49], hepatitis E virus [50,51], porcine circovirus type 2 [52], and Ebola virus [53] are regulated by the UPS, and recent studies revealed that the UPS is necessary for the efficient replication of African swine fever virus and human astrovirus [20,47]. Among these viruses, some encode specific proteins that modify the host Ub machinery.…”

“…Ubiquitination has always been associated with protein degradation. However, some atypical linkages and new roles for Ub in viral propagation have emerged in recent years [18][19][20]. In this review, we highlight recent progress in the field that advances our understanding of the molecular regulation of viral propagation by protein ubiquitination.…”

Total Chemical Synthesis of SUMO and SUMO‐Based Probes for Profiling the Activity of SUMO‐Specific Proteases

“…[8] However,t he molecular mechanisms underlying the role of SUMO modification in these processes remain poorly understood, in part due to the slow development of activity-based reagents. [9] In contrast, research in the ubiquitin field has accelerated due to the convenient chemical synthesis of ubiquitin, [10] which has given access to assay reagents and probes [11][12][13][14] Therefore,areliable route towards SUMO-based conjugates is urgently needed to provide the reagents required to visualize and understand the biology of reversible SUMOylation.…”

Merging Art and Science—The 53rd Bürgenstock Conference

“…His group thus developed smart synthetic organic approaches, including a modified native chemical ligation, which can modify specific lysine or cysteine with various ubiquitin derivatives, negating the use of enzymes ,. Those combined approaches have enabled systematic studies that help understand protein degradation by proteases …”