Unfolded protein response

PROTEIN FOLDING SIMPLIFIED JPEG small

UPR simplified JPEG

Unfolded Protein Response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER). The ER is responsible for the folding and modification of secretory and membrane proteins. When the ER cannot keep up with the demand for protein folding, due to an overload of proteins or other stressors, misfolded or unfolded proteins accumulate, triggering the UPR. The UPR aims to restore normal function of the cell by halting protein translation, degrading misfolded proteins, and activating the signaling pathways that increase the production of molecular chaperones involved in protein folding.

Mechanisms

The UPR is mediated by three main signaling pathways, each initiated by a different sensor protein located in the ER membrane: IRE1, PERK, and ATF6. These sensor proteins detect the presence of unfolded proteins and initiate corrective measures.

IRE1 Pathway

IRE1 (Inositol-Requiring Enzyme 1) is a transmembrane kinase and endoribonuclease. Upon activation, IRE1 splices XBP1 mRNA, leading to the production of a potent transcription factor that upregulates genes involved in protein folding, ER-associated degradation (ERAD), and lipid biosynthesis.

PERK Pathway

PERK (PKR-like ER kinase) phosphorylates the eukaryotic initiation factor 2 (eIF2α), which leads to a general decrease in protein synthesis, reducing the load of new proteins entering the ER. However, this phosphorylation also selectively increases the translation of ATF4, a transcription factor that activates genes involved in amino acid metabolism, redox reaction, and apoptosis.

ATF6 Pathway

ATF6 (Activating Transcription Factor 6) is transported to the Golgi apparatus upon ER stress, where it is cleaved by S1P and S2P, two proteases. The cleaved N-terminal fragment of ATF6 moves to the nucleus and activates genes encoding ER chaperones and components of the ERAD pathway.

Physiological and Pathological Roles

The UPR plays a crucial role in the maintenance of cellular homeostasis and the survival of cells under stress. However, chronic activation of the UPR has been implicated in various diseases, including diabetes, neurodegenerative diseases, and cancer. In these contexts, the UPR may fail to restore ER function and instead contribute to cell death or disease progression.

Therapeutic Implications

Understanding the mechanisms of the UPR and its role in disease has led to the development of therapeutic strategies aimed at modulating this pathway. Drugs that enhance the capacity of the ER to fold proteins or that modulate the signaling pathways of the UPR have potential in treating diseases associated with ER stress.

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