UnfoldedProteinReaktion

UnfoldedProteinReaktion is a cellular stress response triggered by the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER). It comprises signaling pathways that aim to restore proteostasis by reducing the load of new proteins, increasing the ER’s folding capacity, and promoting degradation of defective proteins. The response is initiated by three principal ER membrane sensors—PERK, IRE1, and ATF6—that are kept inactive by the chaperone BiP. When misfolded proteins accumulate, BiP dissociates, activating these sensors. Activated PERK phosphorylates eIF2α, which lowers general protein synthesis while selectively increasing translation of stress-related transcripts such as ATF4. IRE1 splices XBP1 mRNA, producing a transcription factor that upregulates chaperones and ER-associated degradation components. ATF6 moves to the Golgi, where it is proteolytically cleaved to release an active transcription factor that also promotes folding and degradation genes. The combined effect is upregulation of molecular chaperones (for example BiP/GRP78), enhancement of ER-associated degradation (ERAD), and a reduction in the production of new proteins.

If ER stress persists and homeostasis cannot be reestablished, the UnfoldedProteinReaktion can trigger apoptotic pathways involving CHOP, JNK signaling, and caspases, contributing to cell death. The pathway is linked to a range of diseases characterized by proteostasis imbalance, including neurodegenerative disorders, diabetes, and liver diseases, as well as aging-related conditions. Experimental models use pharmacological inducers such as tunicamycin or thapsigargin to study downstream effects. The response is evolutionarily conserved among eukaryotes, though tissue-specific differences influence the balance between adaptive and maladaptive outcomes.