TL;DR
Experimental strategies to identify UID degrons that mediate degradation by the catalytic 20S proteasome particle are described and an integrated workflow-spanning degron mapping to functional validation-provides a generalizable framework for uncovering ubiquitin-independent degrons.
This review compares midnolin-directed degradation with proteolysis-targeting chimeras and molecular glue degraders and identifies the design, delivery, and safety principles that will determine whether it becomes a useful ubiquitin-independent complement to existing degraders.
Combined genome-wide CRISPR knockout screening with base editor tiling screens at amino acid resolution reveal molecular rules governing HUWE1 phospho-degron recognition and identify a regulatory gate controlling substrate engagement and illustrate a generalizable strategy for resolving degradation mechanisms of undrug...
This study demonstrates that integrating ubiquitomics provides a superior sensitivity layer for PROTAC safety assessment, capable of uncovering mechanism-based liabilities that escape conventional global proteomic screening.
The UbiSite approach, a refined strategy for site-specific mapping of global ubiquitination using mass spectrometry-based proteomics, offers a robust and versatile platform for comprehensive ubiquitinome profiling with enhanced specificity and depth, enabling new insights into the regulatory roles of ubiquitin across d...
A non-canonical proteolytic function of USP5 is revealed, uncovering a previously unrecognised regulatory axis linking deubiquitinating enzymes to protein maturation, expanding the substrate repertoire for USP5 and providing a framework for identifying protease–substrate relationships in post-translational regulation.
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