Unfolded protein response

Joseph Sambrook, 1988

Unfolded Protein Response, or UPR for short, is a protective mechanism of the cell coupled to the endoplasmic reticulum (ER), resulting from the accumulation of misfolded proteins in the endoplasmic reticulum (Kozutsumi Y et al. 1988). A misregulation of this protein quality control by UPR can be the cause of numerous diseases.

The aim of UPR is to restore normal cell function. This is achieved by suppressing faulty translation processes, by degrading the incorrectly folded proteins and by activating signaling pathways for the enhanced synthesis of so-called chaperones (French chaperones), which are necessary for correct protein folding. Chaperones are formed more frequently at higher temperatures and are therefore also called heat-shock proteins.

If the "Unfolded Protein Response" is not effective within a certain time or the stress situation persists, this leads to programmed cell death by apoptosis.

The protein kinases Ire1 (Inositol-requiring enzyme 1) and PERK (Protein Kinase RNA-like Endoplasmic Reticulum Kinase) as well as the transcription factor ATF6 (Activating Transcription Factor 6) play a central role in the regulation of UPR. These act as sensors that recognise ER stress caused by defective protein folding and control the functions of UPR via different signalling chains.

From an evolutionary point of view, UPR is a highly conserved part of protein quality control that is pronounced in the cells of all eukaryotes. Disorders of UPR may play a role in various neurodegenerative diseases such as Alzheimer's and Parkinson's disease, in metabolic disorders such as diabetes mellitus and obesity, in inflammatory diseases such as regional enteritis (Hooper KM et al. 2019) and in tumor diseases. Especially in the case of glial tumours, which with a proportion of 82% represent the largest group of malignant tumours of the central nervous system, UPR can have a negative influence on the success of treatment, as resistance to therapy can develop, which can lead to the survival of the degenerated cells.

1. Grootjans J et al (2016) The unfolded protein response in immunity and inflammation. Nat Rev Immunol 16:469-484.
2. Hooper KM et al (2019) Interactions Between Autophagy and the Unfolded Protein Response: Implications for Inflammatory Bowel Disease. Inflammatory bowel disease 25:661-671.
3. Kozutsumi Y et al. (1988) The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature 332: 462-464