Description: The unfolded protein response (UPR) is a cellular stress mechanism activated in the endoplasmic reticulum (ER) when there is an accumulation of misfolded or non-functional proteins. This process is crucial for maintaining cellular homeostasis and ensuring that proteins fold correctly. The UPR has three main signaling pathways: the IRE1 pathway, the PERK pathway, and the ATF6 pathway. Each of these pathways activates different genes that help restore normal ER function by promoting proper protein folding, increasing the degradation of misfolded proteins, and, in extreme cases, inducing apoptosis if the damage is irreparable. The UPR is not only fundamental in cellular biology but is also implicated in various pathologies, including neurodegenerative diseases, diabetes, and cancer. Its study has allowed for a better understanding of how cells respond to adverse conditions and how these responses can be manipulated to develop new therapies. In summary, the unfolded protein response is an essential defense system that enables cells to adapt to stress situations and maintain their functionality.
History: The unfolded protein response was first identified in the 1990s when researchers began to understand the role of the endoplasmic reticulum in protein processing. In 1992, the IRE1 pathway was discovered in yeast, marking a milestone in research on endoplasmic reticulum stress. Subsequently, the other two main pathways, PERK and ATF6, were identified, allowing for a more comprehensive understanding of this cellular process. Over the years, the UPR has been the subject of numerous studies that have revealed its importance in health and disease.
Uses: The unfolded protein response is used in biomedical research to better understand diseases related to endoplasmic reticulum stress. For example, its role in neurodegenerative diseases such as Alzheimer’s and Parkinson’s is being investigated, where the accumulation of misfolded proteins is a key factor. Additionally, the UPR is studied in the context of cancer, as tumor cells often experience endoplasmic reticulum stress due to their rapid proliferation. Manipulating the UPR could offer new therapeutic strategies.
Examples: An example of the application of the unfolded protein response is the use of PERK pathway inhibitors in the treatment of certain types of cancer, where the goal is to reduce the survival of tumor cells that rely on this pathway to survive stress. Another case is the study of the UPR in metabolic diseases, such as type 2 diabetes, where endoplasmic reticulum dysfunction has been observed to contribute to insulin resistance.
