Protein canonical ubiquitination is a process of post-translational modification, whereby a 76-residue ubiquitin (Ub) protein is covalently attached to lysine residues on target proteins, and which is tightly controlled by conjugating (E1, E2, E3) and deubiquitylating (DUBs) enzymes. Furthermore, a number of ubiquitin-like (UBL) modifiers (NEDD8, SUMO, ISG15, UFM1, FAT10, URM1) have also been identified. The study of canonical Ub and UBL proteins has led to a greater understanding of how cells maintain homeostasis and respond to stress, and has implications for the development of treatments for diseases such as cancer and neurodegeneration. There is increasing evidence for non-canonical ubiquitination, which deviates from the conventional ubiquitin-proteasome system (UPS) pathway through formation of Ub chains with atypical linkages or UBL modifiers, Ub attachment to serine, threonine, or cysteine residues, non-protein targets, and post-translational modification of the Ub protein itself. Such non-canonical ubiquitination has been implicated in a variety of cellular processes and can have different consequences depending on the type of modification and context in which it occurs.

In the years since the discovery of the UPS system, great progress has been made in identifying individual proteins and pathways involved in canonical Ub and UBL protein modification. There is nevertheless much still to learn about how and why non-canonical ubiquitination pathways are regulated and coordinated within cells. Additionally, there is a need to develop better tools and methods for studying these processes in detail, including using protein mass spectrometry-based techniques and Ub and UBL-oriented chemical reagents. To address these challenges, researchers use multi-disciplinary approaches combining biochemistry with molecular, chemical, structural, and systems biology. By integrating data from multiple sources and using dedicated analytical tools as in “ubiquitomics”, researchers can gain a more holistic understanding of non-canonical Ub and UBL protein system components and functions. This includes developing new workflows that will enable a better understanding of Ub/UBL pathways and their translational potential, including the mapping of reactive sites, developing using high-throughput screening methods to identify potential substrates and drug targets, or leveraging artificial intelligence and machine learning to analyze large datasets.

This Research Topic aims to expand the knowledge on the promising, recent, and novel research trends in the non-canonical Ub and ubiquitin-like field. Specific themes that we would like contributors to address may include, but not limited to:

1. New findings or discoveries about non-canonical Ub and ubiquitin-like studies

2. Development and expansion of the ubiquitomics toolbox and methodologies, such as activity-based protein profiling (ABPP), GG-peptidomics, structural ubiquitomics, etc.

3. Development and expansion of the Ub and UBL-oriented chemical reagents, such as model substrates, small-molecule inhibitors, activity-based probes, etc.

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Frontiers in Molecular Biosciences

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