RESDOC (Resilient and Just Systems Doctoral Project) is an international doctoral training project at the University of Helsinki in Finland. It brings together interdisciplinary and cross-sectoral res...

Targeted protein degradation (TPD) has emerged as a powerful strategy to eliminate disease-relevant proteins, yet current approaches remain largely constrained to hijacking ubiquitin ligases. We previously introduced ByeTACs, bifunctional molecules that directly recruit proteins to the proteasome for E-ligase independent degradation. Here, we report “Truly” degraders, a new class of dual-mechanism molecules that combine a ligand for the proteasomal receptor Rpn13 with a ligand for cereblon (CRBN) to simultaneously engage both ubiquitin-independent and ubiquitin-dependent degradation pathways. Structure-guided design identified an optimal linker length that supports efficient substrate processing, with the PEG4 derivative (Truly-4) inducing robust depletion of both Rpn13 and CRBN in several cancer cell types. Remarkably, Truly-4 is the first noncovalent small molecule shown to degrade full-length Rpn13, a target previously approached using covalent or domain-restricted strategies. Mechanistic studies confirmed that degradation of Rpn13 proceeds via CRBN-dependent E3 ligase activity, whereas CRBN degradation occurs through an E-ligase independent process, consistent with a ByeTAC mechanism. Importantly, Truly-4 induces selective cytotoxicity in hematologic and solid cancer cell lines but not in healthy cells, despite comparable Rpn13 depletion, indicating that dual degradation can uncouple target engagement from toxicity. These findings establish a generalizable framework for engineering bifunctional degraders that program the proteasome to execute parallel degradation mechanisms and highlight proteasome receptors as druggable nodes for selective destruction of disease-relevant proteins.

Integral membrane proteins face unique folding challenges in the endoplasmic reticulum (ER) due to their hydrophobic transmembrane domains and complex topologies. Membrane protein misfolding disrupts ...

Position Title: Postdoctoral Research Associate - Ames National Laboratory Appointment Type: Post Doc/Trainee Job Description: Summary of Duties and Responsibilities: As a U. S. Department of Energy (...

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Nature Chemical Biology - Engineered aminoacyl-tRNA synthetase (aaRS) mutants have been developed that facilitate ultrafast bioorthogonal noncanonical amino acid tagging (BONCAT) of newly...

N-glycosylation of secretory pathway proteins in the ER is crucial for their maturation and quality control. Recent insights into the enzymes and chaperones that facilitate N-glycosylation have expand...

The Alzheimer's Association calls on HHS Secretary Kennedy to stop dangerous fabrications about the state of Alzheimer’s and dementia research.