ER-nucleus signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals that conveys information from the endoplasmic reticulum to the nucleus, usually resulting in a change in transcriptional regulation. [GOC:mah]

The ER-nucleus signaling pathway is a crucial communication route between the endoplasmic reticulum (ER) and the nucleus, two key cellular compartments. This pathway plays a vital role in coordinating a wide range of cellular processes, including gene expression, protein synthesis, lipid metabolism, and stress response. Here’s a detailed breakdown of the pathway:

1. **Signal initiation:** The pathway is triggered by various stimuli, including changes in cellular environment (e.g., nutrient availability, stress conditions), or alterations in ER homeostasis (e.g., accumulation of unfolded proteins, changes in calcium levels).

2. **ER stress sensors:** Specialized proteins residing in the ER, known as stress sensors, detect these stimuli. The most prominent examples include IRE1α, PERK, and ATF6.

3. **Signal transduction:** Upon sensing stress, these sensors activate distinct signaling cascades.

* **IRE1α:** This transmembrane kinase/RNase dimerizes and activates its RNase activity, leading to the splicing of a specific mRNA, XBP1. The spliced XBP1 mRNA encodes a transcription factor that promotes expression of genes involved in ER protein folding and degradation.

* **PERK:** This kinase phosphorylates the eukaryotic initiation factor 2α (eIF2α), which inhibits protein translation, thus reducing the load on the ER. PERK also activates ATF4, a transcription factor that induces the expression of genes involved in amino acid metabolism and stress response.

* **ATF6:** This transcription factor is normally localized to the ER membrane. Upon activation, it translocates to the Golgi apparatus, where it is cleaved and releases a transcription factor that enters the nucleus. ATF6 activates genes involved in ER chaperone proteins, lipid biosynthesis, and protein degradation.

4. **Nuclear signaling:** Activated transcription factors (e.g., XBP1, ATF4, ATF6) translocate to the nucleus and bind to specific DNA sequences, regulating the expression of target genes.

5. **Cellular response:** The orchestrated transcriptional changes triggered by these signaling pathways result in a multifaceted cellular response, including:

* **Adaptation:** Increasing the capacity of the ER to handle protein folding and degradation, restoring ER homeostasis.
* **Stress response:** Activating stress-protective mechanisms, such as autophagy and apoptosis.
* **Signaling to other cellular pathways:** Integrating with other signaling pathways to coordinate a broader cellular response.

6. **Feedback mechanisms:** The ER-nucleus signaling pathway is tightly regulated by intricate feedback mechanisms, ensuring an appropriate response and preventing excessive or prolonged stress.

The ER-nucleus signaling pathway is a complex and highly regulated system that is essential for maintaining cellular homeostasis. Its malfunction can lead to a wide range of diseases, including metabolic disorders, neurodegenerative diseases, and cancer.'
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Proteins (1)

Compounds (5)