Ubiquitination, the unique post-translational modification, involves the reversible conjugation of single ubiquitin or various kinds of ubiquitin chains. Ubiquitination can be classified as monoubiquitination, multi-monoubiquitination, and polyubiquitination according to the number and topology of ubiquitin molecules that are conjugated to the substrate. Eight homotypic polyUb linkages are known to exist and are linked via the C terminus of donor ubiquitin and any of the seven lysine residues (Lys6, Lys11, Lys27, Lys33, Lys48, and Lys63) or the amino terminal methionine residue (Met1) of the acceptor ubiquitin. The complexity of ubiquitin signaling is augmented by polyUb chains with distinct topologies. Further complexity is provided by post-translational modification of ubiquitin (for example, phosphorylation and/or acetylation) and by linking ubiquitin to other ubiquitin-like molecules (for example, SUMO, NEDD8 and ISG15).
These ubiquitination modifications, termed ubiquitin code, with E2/E3 ligase complexes corresponding to “writers” of the code and deubiquitinating enzymes (DUBs) “erase” the code. The accurate interpretation of ubiquitin code is closely related with protein turnover, subcellular localization, interactions and activities. Thus, ubiquitination is involved in basically all cellular processes: cell growth and differentiation, cell cycle and division, cell death, endocytosis, and protein secretion. The deregulation between ubiquitylation and deubiquitylation is linked to the pathogenesis of a number of human diseases, such as cancer, and neurodegenerative, inflammatory and metabolic disorders.
Recently, identification of novel chain topologies, development of mass spectrometry-based methods, and in-depth study of critical E3 or DUBs in various diseases have improved our understanding of how ubiquitylation establishes precise communication within cells. For example, M1 type ubiquitin chain, which is specifically edited by LUBAC, and specifically removed by OTULIN, exerts in inflammation, infection, and vascular development. The K11-linked chains depends on an essential E3, the anaphase promoting complex (APC/C), and shows important regulatory roles in cell division. However, there are still many problems remain poorly understood. For example, the formation of various ubiquitin chains, their recognition mechanisms, , their biological effects, as well as their own regulatory mechanisms remain unclear. Moreover, deciphering the ubiquitin code is urgent for the development of selective pharmacological agents targeting the Ub system. Currently, proteolysis targeting chimera (PROTAC) has been developed for inducing target protein degradation, and it has emerged as a novel therapeutic modality in drug discovery.
This Research Topic aims to provide a fundamental presentation of the current status of our understanding on the molecular mechanisms involved in protein de/ubiquitination and human diseases. We welcome the submission of Original Research, Methods, Review and Mini-Review articles that cover, but are not limited to, the following topics:
-The pathogenesis underlying abnormality in protein homeostasis-regulating machine;
-Discovery of candidate molecular targeted drugs;
-Editing and interpretation of the ubiquitin code;
-Ubiquitin code deciphering with novel technology;
-Modifications of ubiquitin molecule and new functional analysis;
-Emerging insights into bacterial/viral ubiquitin ligases and deubiquitinases;
-Degradation of target proteins and related drug research by PROTAC technology.
Ubiquitination, the unique post-translational modification, involves the reversible conjugation of single ubiquitin or various kinds of ubiquitin chains. Ubiquitination can be classified as monoubiquitination, multi-monoubiquitination, and polyubiquitination according to the number and topology of ubiquitin molecules that are conjugated to the substrate. Eight homotypic polyUb linkages are known to exist and are linked via the C terminus of donor ubiquitin and any of the seven lysine residues (Lys6, Lys11, Lys27, Lys33, Lys48, and Lys63) or the amino terminal methionine residue (Met1) of the acceptor ubiquitin. The complexity of ubiquitin signaling is augmented by polyUb chains with distinct topologies. Further complexity is provided by post-translational modification of ubiquitin (for example, phosphorylation and/or acetylation) and by linking ubiquitin to other ubiquitin-like molecules (for example, SUMO, NEDD8 and ISG15).
These ubiquitination modifications, termed ubiquitin code, with E2/E3 ligase complexes corresponding to “writers” of the code and deubiquitinating enzymes (DUBs) “erase” the code. The accurate interpretation of ubiquitin code is closely related with protein turnover, subcellular localization, interactions and activities. Thus, ubiquitination is involved in basically all cellular processes: cell growth and differentiation, cell cycle and division, cell death, endocytosis, and protein secretion. The deregulation between ubiquitylation and deubiquitylation is linked to the pathogenesis of a number of human diseases, such as cancer, and neurodegenerative, inflammatory and metabolic disorders.
Recently, identification of novel chain topologies, development of mass spectrometry-based methods, and in-depth study of critical E3 or DUBs in various diseases have improved our understanding of how ubiquitylation establishes precise communication within cells. For example, M1 type ubiquitin chain, which is specifically edited by LUBAC, and specifically removed by OTULIN, exerts in inflammation, infection, and vascular development. The K11-linked chains depends on an essential E3, the anaphase promoting complex (APC/C), and shows important regulatory roles in cell division. However, there are still many problems remain poorly understood. For example, the formation of various ubiquitin chains, their recognition mechanisms, , their biological effects, as well as their own regulatory mechanisms remain unclear. Moreover, deciphering the ubiquitin code is urgent for the development of selective pharmacological agents targeting the Ub system. Currently, proteolysis targeting chimera (PROTAC) has been developed for inducing target protein degradation, and it has emerged as a novel therapeutic modality in drug discovery.
This Research Topic aims to provide a fundamental presentation of the current status of our understanding on the molecular mechanisms involved in protein de/ubiquitination and human diseases. We welcome the submission of Original Research, Methods, Review and Mini-Review articles that cover, but are not limited to, the following topics:
-The pathogenesis underlying abnormality in protein homeostasis-regulating machine;
-Discovery of candidate molecular targeted drugs;
-Editing and interpretation of the ubiquitin code;
-Ubiquitin code deciphering with novel technology;
-Modifications of ubiquitin molecule and new functional analysis;
-Emerging insights into bacterial/viral ubiquitin ligases and deubiquitinases;
-Degradation of target proteins and related drug research by PROTAC technology.
