Practice question

Inability to achieve native conformation triggers layered proteostasis network aimed at restoring balance and if impossible eliminating dangerous species. Initially, chaperone BiP binds exposed hydrophobic stretches, UGGT reglucosylates non-native N-glycoproteins returning them to calnexin-calreticulin cycle for additional attempts at oxidative folding assisted by PDI family, ERp57, Ero1 and peptidyl-prolyl isomerases. Kinetic competition with slow mannosidases EDEM1-3 acts as timer: prolonged residence leads to progressive removal of terminal mannoses preventing reglucosylation and generating degradation signal with exposed α1-6 mannose. Degradation lectins OS-9 and XTP3-B recognize trimmed glycans and deliver clients to Sel1L-Hrd1 and Doa10 ubiquitin ligase complexes. Retrotranslocation via Derlin1-3 or Hrd1 channels, polyubiquitination by Ubc6/7 E2 enzymes, extraction by hexameric ATPase Cdc48/p97 using ATP hydrolysis and degradation by cytosolic 26S proteasome removes client. Persistent overload saturates ERAD activating unfolded protein response sensors IRE1, PERK and ATF6 that upregulate chaperones, expand ER volume, attenuate translation and may induce apoptosis via CHOP transcription factor when stress remains unresolved and adaptation fails to restore homeostasis. Additional coordination with cellular stress pathways ensures fidelity, prevents aggregation, and links trafficking to growth control and proteostasis maintenance across diverse cell types and developmental stages.