The ubiquitin system has become synonymous with the modification of lysine residues. However, the substrate scope and diversity of the conjugation machinery have been underappreciated, bringing us to an epoch in ubiquitin system research. The striking discoveries of metazoan enzymes dedicated toward serine and threonine ubiquitination have revealed the important role of nonlysine ubiquitination in endoplasmic reticulum–associated degradation, immune signaling and neuronal processes, while reports of nonproteinaceous substrates have extended ubiquitination beyond the proteome. Bacterial effectors that bypass the canonical ubiquitination machinery and form unprecedented linkage chemistry further redefine long-standing dogma. While chemical biology approaches have advanced our understanding of the canonical ubiquitin system, further study of noncanonical ubiquitination has been hampered by a lack of suitable tools. This Perspective aims to consolidate and contextualize recent discoveries and to propose potential applications of chemical biology, which will be instrumental in unraveling this new frontier of ubiquitin research.
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We thank members of the Virdee laboratory and I. Kelsall for critical feedback on our manuscript. S.V. and D.S. are funded by the UK Medical Research Council (grant no. MC_UU_12016/8). We also acknowledge pharmaceutical companies supporting the Division of Signal Transduction Therapy (Boehringer-Ingelheim, GlaxoSmithKline and Merck KGaA).
S.V. is a founder and shareholder of Outrun Therapeutics, a biotech company investigating the ubiquitin system. D.R.S. declares no competing interests.
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Squair, D.R., Virdee, S. A new dawn beyond lysine ubiquitination. Nat Chem Biol 18, 802–811 (2022). https://doi.org/10.1038/s41589-022-01088-2