Ubiquitin–proteasome system & protein homeostasis

E1 activates ubiquitin, E2 carries it, and one of ~600 E3 ligases (CRL4-CRBN, VHL, MDM2, SCF-FBXW7, APC/C) attaches it to a substrate lysine; K48 chains send substrates to the 26S proteasome, whose β5 subunit is the target of bortezomib, carfilzomib and ixazomib. Deubiquitinases (USP7, USP14) reverse tagging. Plasma cells and myeloma depend on proteasome capacity to clear misfolded immunoglobulin; inhibition triggers the unfolded protein response (PERK, IRE1, ATF6) and death, and stabilises IκB to shut NF-κB. Cereblon modulators (thalidomide, lenalidomide, pomalidomide; CELMoDs iberdomide, mezigdomide, golcadomide) are molecular glues that redirect CRL4-CRBN to degrade IKZF1/3. PROTACs (vepdegestrant for ER, ARV-766 for AR, BGB-16673 for BTK) link a target ligand to an E3 ligand. Oncogenic lesions in the system: FBXW7 loss stabilises MYC, cyclin E and NOTCH; SPOP mutations in prostate; VHL loss stabilises HIF; MDM2 amplification degrades p53. HSP90 and chaperones buffer mutant kinases; HSP90 inhibitors mostly failed on toxicity.